Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:24]
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Reactant: CCCCCCCCCCCC(=O)OC
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 6.5 ppm) and 556 g of methyl laurate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 35.4 g of a 5% by weight sodium methoxide methanol solution and 0.44 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 150° C. as a reaction temperature. After the temperature reached 150° C., the reaction was carried out under a nitrogen stream at normal pressure. At the time point when the spot of methyl laurate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 8 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monolaurate.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)(C(C)(C)C)(C)C.[F-].C[N+](C)(C)C>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH:16]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:19]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O[Si](C)(C)C(C)(C)C)C1
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
To a solution of tert-Butyl 3-(2-{[tert-butyl(dimethyl)silyl]oxy}-5-chlorophenyl)azetidine-1-carboxylate (Preparation 238, 3.1 g, 7.79 mmol) in tetrahydrofuran (80 ml) was added tetramethylammonium fluoride (1.0 g, 10.74 mmol). The mixture was stirred at room temperature for 18 hours before concentrating in vacuo. The residue was partitioned between tert-butyl methyl ether (100 ml) and aqueous sodium hydroxide solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give a reddish brown oil, 2.33 g. This was purified by column chromatography (100 g of silica) eluting with heptane:ethyl acetate (6:4, by volume) to afford the title compound as a reddish brown gum, 850 mg, 38% yield.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]([CH2:18][C:19]1([NH:22][CH3:23])[CH2:21][CH2:20]1)[C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:24]=O.Cl>C(O)=O.C(O)C.CCOCC>[ClH:17].[CH2:3]([N:10]([CH2:18][C:19]1([N:22]([CH3:24])[CH3:23])[CH2:20][CH2:21]1)[C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNC1(CN(Cc2ccccc2)c2ccc(Cl)nc2)CC1
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: O=CO
Solvent: CCOCC
Product: CN(C)C1(CN(Cc2ccccc2)c2ccc(Cl)nc2)CC1
Temperature: 70 °C

Procedure:
3.1 g of the base of the compound of Example 17 are dissolved in 60 ml of formic acid. 60 ml of 37% aqueous formaldehyde solution are added and the mixture is heated for 4 hours at 70° C. Concentration to dryness is carried out, and the residue is taken up in 50% aqueous potassium carbonate solution and extraction is carried out with dichloromethane. The organic phase is dried over sodium sulphate, concentration is carried out, and the residue is chromatographed on silica gel (dichloromethane/acetone: 96/4). A fraction consisting of 0.48 g of base of the expected compound is isolated which, after dissolution in 5 ml of ethanol and addition of hydrochloric acid solution in ether, allows, after filtering off a precipitate and drying, 0.4 g of the expected compound to be obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(C)CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 17.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.73 g) and 5-amino-2-[4-[N-(2-hydroxyethyl)-N-methylamino]piperidin-1-yl]benzonitrile (0.65 g), the title compound (0.2 g) was obtained, melting point: 186° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[H][H].[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CNCCN1C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Yield: 90.3 %

Procedure:
A solution of ethyl 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazine-2-carboxylate (69.0 g) in acetic acid (AcOH, 500 ml) was subjected to catalytic reduction using platinum dioxide (4.0 g) at 40° C. in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in H2O (800 ml) and the solution was washed with Et2O (500 ml×2). To the aqueous layer was added NaHCO3 to adjust the pH of the solution to 8 and the solution was extracted with AcOEt (800 ml×2). The combined organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo to give 62.8 g of ethyl 1-tert-butoxycarbonyl-piperazine-2-carboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([NH:14]C(=O)C)=[CH:9][C:8]=2[CH3:18])[N:6]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:14][C:10]1[CH:9]=[C:8]([CH3:18])[C:7]([C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[C:12]([CH3:13])[CH:11]=1
Reactant: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(N)cc(C)c1-c1csc(N)n1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A solution of N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (1.31 g, 5.0 mmol) in 2N HCl (25 mL) was refluxed for 1 h and then cooled to 0° C. Na2CO3 was carefully added to the stirring mixture until no gas evolvement, and the pH was further adjusted to 8. The mixture was then extracted with EtOAc (4×50 mL), and the combined organic phase was dried over Na2SO4, filtered, concentrated, and provided 4-(4-amino-2,6-dimethylphenyl)thiazol-2-amine (1.03 g, 93.9% yield). The crude product was used for next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([NH:17][C:28]([NH:27][C:25](=[O:26])[C:24]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:23]=3[F:22])=[O:29])=[CH:18][C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 53.7 %

Procedure:
A solution containing 2.25 g (6.6 m moles) of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline in 45 ml of toluene was placed under a nitrogen atmosphere and heated to 70° C. via an addition funnel was then added 1.82 g (9.9 m moles) of 2,6-difluorobenzoylisocyanate in 5 ml of toluene. The resulting mixture was then stirred at 70° C. for 45 min. and then cooled to room temperature. It was then cooled below 0° C. and filtered. The collected white white solid was dried under vacuum to afford 1.86 g of the desired product, m.p. 237°-239° C. NMR: (DMSO-d6): δ6.47 (d, J=8 Hz, 1H)- 7.0-8.6 (m, 10H), 10.40 (broad s, 1H), 11.60 (broad s, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]C(=O)C)[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])=[O:8])(=O)C.[OH-].[Na+]>>[C:7]([NH:9][C:10]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:28])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:8])[C:6]1[C:5](=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:4]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)=O)cc1NC(=O)c1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2O)c1)c1ccccc1O
Yield: 85 %

Procedure:
By the procedure similar to that described in Example 5, methyl 2,4-bis(2'-acetoxybenzamido)-benzoate obtained in Example 6 was hydrolized with the aid of sodium hydroxide. Recrystallization of the hydrolized product from a mixture of dioxane and water gave 2,4-bis(salicylamido)-benzoic acid having a melting point between 250° - 252°C (decomposition). (Yield; 85%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)[O:26][C@@H:25]([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:24][O:23]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:28][CH2:27][C@H:25]([OH:26])[CH2:24][OH:23])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC[C@H](O)CO)CC1

Procedure:
In analogy to the procedure described for example 167A and 167B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (prepared from 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride) gave the title compound as an white foam. MS: 401.3 (MH+, 2Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]([N:18]=[C:19]=[O:20])[CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:20])=[CH:13][CH:14]=1
Reactant: Clc1ccc(CNC2CCCC2)cc1
Reactant: CCCN=C=O
Product: CCCNC(=O)N(Cc1ccc(Cl)cc1)C1CCCC1
Yield: 73.4 %

Procedure:
In a manner analogous to that described in Example 1, 31 g of N-4-chlorobenzyl-N-cyclopentylamine were reacted with 13 g of propyl isocyanate. 32 g of N-4-chlorobenzyl-N-cyclopentyl-N'-propylurea were obtained. Melting point: 103°-105° C.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([OH:14])=O)[CH:11]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[NH2:56][CH2:57][C@@H:58]([OH:60])[CH3:59]>O.CN(C)C=O>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([NH:56][CH2:57][C@@H:58]([OH:60])[CH3:59])=[O:14])[CH:11]=1
Reactant: C[C@H](O)CN
Reactant: Cc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1CNc1cc(C(=O)NC[C@H](C)O)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (30 g, 0.0928 mol) and 30 g diisopropylethylamine (30 g, 0.233 mol) were added to dimethylformamide (DM) (250 ml). o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (36 g, 0.112 mol) was added. The mixture was stirred for 15 min at room temperature. (S)-1-amino-2-propanol (8.4 g, 0.112 mol) was added and the stirring was continued for 1 h at room temperature. Water (100 ml) was added and the reaction mixture was heated to 70° C. The product was precipitated by slowly adding more water (200 ml). The mixture was then stirred for 5 h at 65-70° C. After cooling to room temperature the product was filtered off and washed with 40% methanol solution. 33.7 g of the compound of the invention was obtained.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]2[CH2:15][CH2:14][N:13]([CH3:16])[C:12]2=[N:17][C:18]#[N:19])[C:9]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:8]=2[O:7][C:6]1([CH3:27])[CH3:26])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:18]([N:17]=[C:12]1[N:13]([CH3:16])[CH2:14][CH2:15][N:11]1[C:10]1[C:9]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:8]=2[O:7][C:6]([CH3:27])([CH3:26])[CH:5]=1)#[N:19]
Reactant: CC(=O)O[C@H]1[C@H](N2CCN(C)C2=NC#N)c2cc(C#N)ccc2OC1(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 71.7 %

Procedure:
To a suspension of trans-3-acetoxy-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.45 g) in toluene (9 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 ml), and the reaction mixture was stirred at 100° C. for 2 hours and 40 minutes. The solvent was removed under reduced pressure. The residue was poured into water (30 ml) and then extracted with ethyl acetate (45 ml). The organic layer was washed with brine (30 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 4-(2-cyanoimino-3-methylimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.27 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+].[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([I:12])[CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
4-Bromo-2-nitroaniline (14.3 g, 0.0659 mol) was added in one portion to iodine (17.6 g, 0.0692 mol) dissolved in ethanol (300 ml), followed by silver (I) sulphate (20.4 g 0.0659 mol). After stirring at ambient temperature for 18 hours the reaction was filtered and the solid obtained was washed with dichloromethane until all the orange product had dissolved. The combined filtrates were evaporated in vacuo and the resulting solid was washed with diethyl ether/40-60 Petroleum ether (1:1) and filtered to give 4-bromo-2-iodo-6-nitroaniline as an orange solid (19.8 g, 88%), which was used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:14](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:6])[OH:15]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)C(=NO)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 18.24 gm (90.3 mMol) 2-(trimethylsilyl)ethyl acetoacetate in 10 mL acetic acid at −4° C. was added a solution of 6.85 gm (99.3 mMol) sodium nitrite in 30 mL of water dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature while stirring. After 2 hours the reaction mixture was diluted with 100 mL ethyl acetate and washed twice with 50 mL portions of saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residual was dissolved in toluene and concentrated under reduced pressure twice to azeotropically remove any remaining acetic acid. The residual oil was finally subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 12.04 gm (58%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OCC1C=CC=CC=1)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([O:11][C:12](=[O:28])[CH2:13][N:14]([C:42](=[O:43])[C@H:40]([CH3:41])[NH2:39])[CH:15]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1cc2c(cc1OC)C(NCC(=O)OC(C)(C)C)CC2
Agent: O=C(O)C(=O)O
Product: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Yield: 48.5 %

Procedure:
By reacting 7 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate with 4.8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 5, there is obtained 4 g of L-alanyl-N-(5,6-dimethoxy-indan-1-yl)glycine tert-butyl ester oxalate as colorless amorphous powder.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[OH:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH:20]([C:22](OC)=[O:23])[CH2:19][C:18]=3[CH:26]=2)=[CH:10][CH:9]=1)[CH3:7]>CO>[OH:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH:20]([C:22]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:23])[CH2:19][C:18]=3[CH:26]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: COC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1
Reactant: C=CCN
Solvent: CO
Product: C=CCNC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 ml of 2-propenylamine was added to a mixture of 5.0 g of 6D and 100 ml of methanol. The solution was stirred at room temperature overnight. The volatile materials were evaporated under reduced pressure. The residue was stirred with 50 ml of ether, the solid was collected and dried in a vacuum oven to give 6, mp: 122°-124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:9](Cl)=[O:10].[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:9]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:21]1)=[O:10]
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: Cc1ccccc1C(C(=O)Cl)c1ccccc1C
Product: Cc1ccccc1C(C(=O)N[C@H]1CCN(CCc2ccc(F)cc2)C1)c1ccccc1C
Yield: 15 %

Procedure:
2,2-Bis(2-methylphenyl)acetyl chloride (0.74 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 53 to give (S)-2,2-bis(2-methylphenyl)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)acetamide (0.13 g), melting point 108-110° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN2CCCC2)c1=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.6 %

Procedure:
To a stirred solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.1 g) in N,N-dimethylformamide (3 mL), N-(2-chloroethyl)-pyrrolidine, hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction was stirred under nitrogen at 80° C. for 12 h. After 2 h additional batches of N-(2-chloroethyl)-pyrrolidine hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction mixture was stirred at 100° C. for 10 h and then at 90° C. for 10 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column—acetonitrile/0.1% ammonia mobile phase) afforded the title compound as a solid (34 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:64]2[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]3[CH:48]=[CH:49][C:50]([O:53][C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[CH:51][CH:52]=3)[CH2:62][CH2:63]2)=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to 4-fluorobenzoic acid (44 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively and, after 10 mins, N-(2-oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-{2-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 49% yield. LC-MS purity: 97%, 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (m, 4H), 7.2 (m, 4H), 7.1 (m, 4H), 4.3 (s, 2H), 3.6 (m, 8H).