Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(C([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=CC=1.Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([N:11]([CH2:10][CH2:9][CH3:8])[CH2:20][C:13]2[CH:12]=[CH:17][C:16]([O:18][CH2:40][CH2:41][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:15][CH:14]=2)[CH:17]=1
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: CCCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 160.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH:28][NH2:29])(=[O:27])=[O:26]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:29]/[NH:28][S:25]([CH3:24])(=[O:27])=[O:26])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CS(=O)(=O)NN
Product: C/C(=N\NS(C)(=O)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and methanesulfono-hydrazide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 7.82 (m, 2H), 7.85 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 3.20 (s, 3H), 2.35 (s, 3H)). LCMS (method B): [MH]+=446, tR=1.37 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9][C:7]=2[N:8]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1ccc2sc(COC)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2cc(C(=O)O)ccc2s1

Procedure:
A mixture of 2.1 g (8.36 mMol) of ethyl 2-methoxymethyl-benzothiazole-5-carboxylate and 16 ml of 2N sodium hydroxide solution was stirred into 60 ml ethanol for 1 hour at room temperature. Then the alcohol was distilled off, the crude product was taken up in 20 ml water, washed with 50 ml diethylether and the aqueous phase was acidified with concentrated hydrochloric acid whilst being cooled with ice. The pinkish-beige compound thereby precipitated was suction filtered, washed with water and dried. Yield: 1.6 g (86% of theory), Rf value: 0.12 (silica gel; dichloromethane/ethanol=29:1)
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:52][NH:51][C:50]1=[O:53])=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:52][NH:51][C:50]1=[O:53])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CNC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CNC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 36.4 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (331 mg, 0.66 mmol), (2R,4S)-N-allyloxycarbonyl-2-(2-azetidinon-3-ylmethyl)-4-mercaptopyrrolidine (180 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.12 ml, 0.66 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 36.3%) in the form of foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]3[CH:20]=[N:21][O:22][C:18]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6-aminoquinoline (0.38 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.56 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(6-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.79 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 170–171° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=[C:12]3[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a yellow foam. LC/MS 365.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed TH F (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and triethylamine (1.26 g, 13 mmol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M+H)+=356.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][Br:22])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)CBr
Yield: 102.5 %

Procedure:
To a mixture of tert-butyl 2-aminobenzoate (5.79 g.), triethylamine (3.99 g.) in methylene chloride (100 ml.) was added dropwise bromoacetyl bromide (8.01 g.) over a period of 15 minutes with stirring under ice-cooling at 5° to 10° C. followed by stirring for 1.75 hours at the same temperature. The reaction mixture was washed successively with 1M aqueous solution of citric acid (50 ml.×2), water a satirated aqueous solution of sodium bicarbonate (25 ml.×2), water and an aqueous solution of sodium chloride, dried over magnesium, treated with activated charcoal and then evaporated to give an oil of the title compound (9.65 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[S:31])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Yield: 109.4 %

Procedure:
Estrone methyl ether (2, 17.64 g, 62.2 mmol) was dissolved in 500 mL of dry tetrahydrofuran (THF) and a first portion of Lawesson's reagent (13 g, 32 mmol) was added. The reaction mixture containing suspended solid was heated to reflux for 18 h when all solids dissolved and the solution became salmon red. A second portion of Lawesson's reagent (13 g, 32 mmol) was added and heating continued at reflux temperature for another 18 h. Similarly, a third portion of Lawesson's reagent (13 g, 32 mmol) was added; and after being heated for 18 h, the reaction mixture was cooled and the THF evaporated to give a thick slurry. The slurry was dissolved in a minimum amount of CH2Cl2 and passed through a pad of silica gel to remove a polar by-product of Lawesson's reagent. The eluent was concentrated to afford a bright orange solid which was further purified by column chromatography on silica gel with EtOAc-Hexanes (1:3) as eluent to afford a bright orange solid product (10.5 g, 35 mmol) in 56% yield as the first fraction and then starting material (4 g, 14.0 mmol) in 23% recovery. Crude thione 3 can be further purified by crystallizing from boiling EtOAc, although after column purification it is pure enough for subsequent reactions. 1H NMR (250 MHz, CDCl3) δ 0.94 (s, 3, C-S 8 CH3), 3.78 (s, 3, --OCH3), 6.64-6.75 (m, 2, ArH), 7.22 (d, J=10 Hz, 1 ArH); 13C NMR (250 MHz, CDCl3) δ 273.3 (C=S).
Reaction SMILES: Cl.CN1C2=CCC(=O)C=C2[O:5][CH:4]1[CH2:13]CN.Cl.[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH2:30]>>[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH:30][C:4](=[O:5])[CH3:13]
Reactant: CN1C2=CCC(=O)C=C2OC1CCN
Reactant: CN1C2=CCC(=O)C=C2SC1CCN
Agent: Cl
Product: CC(=O)NCCC1SC2=CC(=O)CC=C2N1C

Procedure:
By replacing 2-(3-methyl-6-benzoxazolinonyl)ethylamine hydrochloride in Example 61 by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, described in French Patent Application 90/11,866, the product of the title is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N:21]4[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]4)=[CH:32][CH:31]=3)=[CH:7][CH:6]=2)=[C:10]([F:16])[CH:11]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Nc2ccc(N)cc2F)cc1
Product: Nc1ccc(Nc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)c(F)c1

Procedure:
Compound 807 was prepared according to the procedure described in Scheme IV from N1-(4-aminophenyl)-2-fluorobenzene-1,4-diamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C24H25FN4O2: 421.20; found 420.98.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:21][OH:22].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]([OH:22])[C:1](=[O:3])[CH3:2]
Reactant: Cc1cccc(Nc2ccccc2CNO)c1C
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N(O)Cc1ccccc1Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Acetyl chloride (0.53 g, 6.8 mmol) is added dropwise at 0° C. to a solution of 2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzenemethanamine (1.64 g, 6.8 mmol) and sodium acetate (840 mg, 10 mmol) in 2:1 dioxane/water (100 ml). The reaction mixture is stirred at room temperature for 30 minutes. The product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated to a residue which is recrystallized from cyclohexane to give pure N-[[2-[(2,3-dimethylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide (1.02 g, 53%); mp 93°-98° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH2:15][CH:17]1[CH2:18][O:19]1
Reactant: Oc1cc(C(F)(F)F)ccc1I
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(I)c(OCC2CO2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A sample of 20 g (0.069 mole) of 2-iodo-5-trifluoromethylphenol was added in portions to a suspension of 0.07 mole of NaH (from 3.36 g of 50% NaH which had been washed free of oil with hexane) in 150 ml of dry DMF under N2. When gas evolution had ceased, a 27 ml (0.347 mole) sample of epichlorohydrin was added dropwise at 5° C. The mixture was heated at 60° C. for 3 hr and allowed to stand at 25° C. for 16 hr. A precipitate was removed by filtration. The filtrate was concentrated to dryness in vacuo. The residue was taken up in ether, washed with water and brine, dried (K2CO3) and the solvent evaporated in vacuo to give 20.4 g (86% yield) of [(2-iodo-5-trifluoromethylphenoxy)methyl]oxirane as an oil.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])=[CH:10][C:9]=2[O:26][CH3:27])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30]>CN1C(=O)CCC1>[OH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:3][CH2:2]3)=[C:9]([O:26][CH3:27])[CH:10]=1)[CH2:23][CH2:22]2
Reactant: CC1(C)CO1
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
A solution of 2-(4-[1,4]diazepan-1-yl-3-methoxy-phenyl)-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (193 mg) and isobutylene oxide (300 mg) in NMP (0.8 mL) was stirred at 65° C. for 16 h. The reaction mixture was purified by preparative HPLC. In this way the product was obtained with molecular weight 439.56 (C25H33N3O4); MS (ESI): 440 (M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH2:29]([O:31][CH:32]([O:43][CH2:44][CH3:45])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C:34]1=[O:42])[CH3:30]>C1(C)C=CC=CC=1.C1COCC1>[CH2:44]([O:43][CH:32]([O:31][CH2:29][CH3:30])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:34]1=[O:42])[CH3:45]
Reactant: CCOC(OCC)N1C(=O)Cc2ccccc21
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2ccccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (48 ml of a 0.5M solution in toluene, 24 mmol) was rapidly added to a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (3.2 g, 11.9 mmol) and 1-diethoxymethyloxindole (4.0 g, 14.9 mmol), (prepared according to Synthesis 1975, 168), in THF (240 ml) at ambient temperature. After 2 hours, the precipitate was filtered off and washed with ether. The filtrate was evaporated. The residue was mixed with the precipitate and partitioned between methylene chloride and water and the organic phase washed with saturated aqueous sodium chloride solution. The organic layer was driied (MgSO4) and the solvent removed by evaporation. The residue was purified by column flash chromatography using methylene chloride/methanol (95/5) as eluent. The purified product was triturated with a mixture of ether and petroleum ether to give 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (4.03 g, 74%) as a red orange solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[N:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:20]1([N:26]2[C:30]([NH2:31])=[CH:29][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>>[CH:20]1([N:26]2[C:30]([NH:31][C:10]([C:8]3[C:7]([NH:13][C:14]4[CH:15]=[N:16][CH:17]=[N:18][CH:19]=4)=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:9]=3)=[O:12])=[CH:29][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: Nc1cc(-c2ccccn2)nn1C1CCCCC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccccn2)nn1C1CCCCC1)c1nc(C2CC2)ccc1Nc1cncnc1
Reaction time: 8 h
Yield: 29 %

Procedure:
To a suspension of 6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (50 mg, 0.2 mmol; intermediate A-5) at r.t under an argon atmosphere were added 2-cyclohexyl-5-pyridin-2-yl-2H-pyrazol-3-ylamine (47 mg, 0.2 mmol) and N-ethyldiisopropylamine (0.1 ml, 0.6 mmol). The yellow suspension was cooled to 0°, and propylphosphonic anhydride (0.31 ml, 1 mmol; 50% in AcOEt) was added. The suspension was stirred at 0° for 30 min. and at r.t overnight. The solvent was evaporated. After silica gel chromatography using a CH2Cl2/MeOH gradient, the product was obtained as yellow solid in 29% yield. MS: M=481.3 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-])=O)=[N:7][CH:8]=1>C(O)(=O)C.Cl.[Zn]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=1
Reactant: CSc1ccc([N+](=O)[O-])nc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CSc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
This nitropyridine (300 mg, 1.8 mmol) was dissolved in a mixed solvent of acetic acid (7 ml) and conc. hydrochloric acid (0.5 ml), and zinc (692 g, 10.6 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent-hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain 158 mg (yield 64%) of 2-amino-5-methylthiopyridine as a pale-yellow powdery crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: BrCC1CC1
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])ccc(OCC2CC2)c1Cl
Temperature: 100 °C
Yield: 93.4 %

Procedure:
2-Chloro-3-methyl-4-nitrophenol (2.71 g) was reacted with bromomethylcyclopropane (3.89 g) in dry DMF (30 ml) in the presence of potassium carbonate (3.99 g), heating the mixture at 100° C. overnight. The DMF was evaporated in vacuo, and the residue was partitioned between 2M HCl and ethyl acetate. The organic extracts were combined and dried (MgSO4) and evaporated to give 2-chloro-3-cyclopropylmethyloxy-6-nitro toluene (3.26 g).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:10][CH:9]=2)[O:4]C1.O.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[OH:23][CH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH:5]=[O:4])=[CH:9][CH:10]=1)[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CC(O)c1ccc(C2OCC(C)(C)CO2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(C=O)c2ccccc12
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 1-[4-(5,5-Dimethyl-1,3-dioxan-2-yl)-1-naphthyl]-3-methyl-1-butanol (1.76 g, 5.35 mmol) in THF (10 mL) was added water (1 mL) and conc. HCl (1 mL). The solution was stirred at room temp. for 16 hours, diluted with NaHCO3-solution (20 mL), and extracted with ether (3×30 mL). The combined organic extracts were dried and concentrated. Flash chromatography (silicagel, hexanes:ethyl acetate, 4:1) provided 900 mg (70%) colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[CH3:22].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Yield: 91 %

Procedure:
A mixture containing 29.9 gm (0.017 mol) of Nα-benzyloxycarbonyl-L-lysine, 30 ml of ethanol, and 9.0 ml of concentrated sulfuric acid in 250 ml of methylene chloride was refluxed for 22.5 hours. The reaction mixture was then cooled to room temperature and basified to pH of about 13 by the careful addition of a saturated aqueous solution of potassium carbonate. The aqueous phase was removed and the organic phase was washed one more time with a saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 29.8 gm (91% ) of ethyl Nα-benzyloxycarbonyl-L-lysinate (II-F) as an oil.