Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[S:48])=[CH:42][CH:41]=1.C(N(CC)CC)C>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:3][C:4]2[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]4[N:16]=[C:15]([CH2:17][O:18][C:19]5[CH:20]=[CH:21][C:22]([CH2:23][CH:24]6[S:28][C:27](=[O:29])[NH:26][C:25]6=[O:30])=[CH:31][CH:32]=5)[N:14]([CH3:33])[C:13]=4[CH:34]=3)=[CH:35][C:36]=2[CH3:37])=[S:48])=[CH:42][CH:41]=1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), 4-chlorophenyl isothiocyanate (102 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and then chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 as the eluant to afford the title compound (215 mg, mp 160-162° C.).
Reaction SMILES: Br[CH:2]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:3]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:24][C:23](=[S:33])[NH:22]1>O1CCCC1>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[C:2]1[S:33][C:23]2=[N:24][C:25]([CH3:32])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH3:13])[N:22]2[CH:3]=1
Reactant: O=CC(Br)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C1=C(C)NC(=S)NC1c1ccccc1OC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C2SC(c3c(Cl)cccc3Cl)=CN2C1c1ccccc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.3 %

Procedure:
A mixture of 2.0 g (7.5 mmol) of α-bromo-2,6-dichlorophenyl-acetaldehyde and 2.08 g (6.8 mmol) of ethyl (RS)-4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate in 40 ml of tetrahydrofuran was stirred at RT for 17 h. Subsequently, the mixture was cooled to 0° C. and the precipitated solid was filtered off, dissolved in 75 ml of conc. acetic acid and heated at reflux while stirring for 24 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate). There were obtained 1.82 g (51%) of ethyl (RS)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43](O)[CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57]>>[ClH:1].[OH:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCOCCOCCOCCOCCO
Product: COc1cc(C(=O)OCCOCCOCCOCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 3,6,9,12-tetraoxatetradecane-1,14-diol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C41H50Cl2F2N3O9: [(M+H)+]836. found: 836.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:23]([O:22][CH3:21])=[N:28][CH:27]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:15][CH2:16][CH2:17]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 2-methoxypyrimidine-5-boronic acid (Frontier Scientific, Inc., Logan, Utah, USA) for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.07 (d, J=8.48 Hz, 1H) 7.97 (d, J=2.03 Hz, 1H) 7.59 (dd, J=8.48, 2.03 Hz, 1H) 4.08 (s, 3H) 3.93-4.06 (m, 1H) 3.18-3.34 (m, 5H) 2.49-2.61 (m, 1H) 2.34-2.47 (m, 3H) 2.03-2.19 (m, 2H). MS: (M+H)+=353.
Reaction SMILES: CC1C=C[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Br[C:17]1[C:18](C(O)=O)=[N:19]C=C[CH:22]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:15]1[N:11]([C:4]2[C:5]([C:6]([OH:8])=[O:7])=[N:19][CH:18]=[CH:17][CH:22]=2)[N:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1ncccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 47 substituting 3-bromo-2-pyridinecarboxylic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C8H6N4O2, 190.10; m/z found 191.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.77 (d, J=4.3 Hz, 1H), 8.26 (dt, J=6.5, 3.3 Hz, 1H), 7.88 (s, 2H), 7.65 (dd, J=8.2, 4.7 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:25])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
1.28 g of 4-(quinolin-2-ylmethoxy)benzoic acid, in 4.6 ml of oxalyl chloride and 3 drops of dimethylformamide are combined in 50 ml of methylene chloride. The mixture is refluxed for 30 minutes and then concentrated in vacuo to give 4-(quinolin-2-ylmethoxy)benzoyl chloride
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])#[CH:23]>C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:23]#[C:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(c2ncnc(C#Cc3ccccc3C(F)(F)F)c2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
1-{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.317 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol) and copper(I)iodide (5 mg, 0.026 mmol) were dissolved in diisopropylethylamine and stirred for 2 min. o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and the mixture stirred under N2 at 70° C. for 18 hours. The yellow suspension turned black. After cooling to room temperature, the reaction mixture was diluted with chloroform (12 ml), passed through a celite plug and concentrated under vacuo. Purification by Flash Chromatography (0-30% Ethyl acetate/Hexanes) gave Compound Dl. Yield 35%. 1H NMR 400 MHz CDCl3 δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7.56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M+H+, 100%)
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>C1COCC1>[NH2:6][C:4](=[S:11])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CCC(N)=O
Solvent: C1CCOC1
Product: COC(=O)CCC(N)=S
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
Methyl succinamate (2 g, 15.2 mmol) was dissolved in dry THF (50 mL) and P2S5 (3.4 g, 15.2 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through a sintered funnel and the clear filtrate was concentrated under reduced pressure to get the crude product, which was further purified by column chromatography (silica gel 60-120 mesh, eluent 50% EtOAc in petroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.25 g, yield 53%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.27 (br s, 2H), 3.72 (s, 3H), 2.96-2.85 (m, 4H). MS (ESI) m/z: Calculated for C5H9NO2S: 147.04. found: 148.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CCN(C(C)C)C(C)C.[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([SH:35])=[CH:29][CH:28]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C:22]2[N:26]3[C:27]4[C:32]([CH:33]=[CH:34][C:25]3=[N:24][N:23]=2)=[CH:31][C:30]([S:35][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:29][CH:28]=4)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Temperature: 80 °C

Procedure:
To 2-Bromothiazole (0.27 mL, 3.0 mmol) in 1,4-dioxane (20 mL) was added iPr2NEt (0.96 mL, 5.5 mmol), and the reaction was degassed with N2 for 10 minutes. 10e (765 mg, 2.8 mmol) was added, followed by Pd2dba3 (63 mg, 0.07 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81 mg, 0.14 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10f.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][CH2:39][C:38]1[C:37]([Cl:36])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 214 mg (0.89 mmol) of 2,6-dichlorobenzyl bromide were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 195 mg of 2-(2,6-dichlorobenzylamino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 48%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21]([OH:23])=O)=[O:17].ON1C(=O)CCC1=O.Cl.[CH3:37][O:38][C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:41].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:37][O:38][C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:41][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:26]([OH:27])=[C:18]([CH:16]=[O:17])[CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1cc(C(=O)O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(O)c(C=O)c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
87 mmol of dicyclohexylcarbodiimide are added to a stirred suspension, cooled to 10° C., containing 80 mmol of 3-formyl-4-hydroxybenzoic acid (prepared according to H. WYMBERG, J. Am. Chem. Soc., 76, 4998, 1954) and 87 mmol of N-hydroxysuccinimide in 320 ml of chloroform. After re-equilibrating to room temperature, the mixture is kept stirring overnight. The precipitate is then filtered. The filtrate is cooled to 8° C. and treated dropwise, with stirring, with a suspension containing 160 mmol of phenylalanine methyl ester hydrochloride and 160 mmol of triethylamine in 100 ml of anhydrous dimethylformamide. The mixture is stirred for 3 hours at 20° C. and then for 5 hours at 50° C. After cooling and evaporation of the solvents, the residue is taken up in 400 ml of ethyl acetate. After washing this solution with 1N hydrochloric acid and then with water, the organic phase is dried and evaporated. The oily residue leads to the expected product by crystallization from toluene.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C@@H:7]([CH2:11][NH:12][C:13]([C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([C@@H:22]3[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]3[C:28](=[O:49])[CH2:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:21])=[O:14])[CH2:6]2)[CH2:3][CH2:2]1.[CH:50]1([CH2:53][Br:54])[CH2:52][CH2:51]1>>[Br-:54].[CH:1]1([CH2:4][N+:5]2([CH2:53][CH:50]3[CH2:52][CH2:51]3)[CH2:10][CH2:9][CH2:8][C@@H:7]([CH2:11][NH:12][C:13]([C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([C@@H:22]3[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]3[C:28](=[O:49])[CH2:29][C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:21])=[O:14])[CH2:6]2)[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: O=C(NC[C@@H]1CCCN(CC2CC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(NC[C@@H]1CCC[N+](CC2CC2)(CC2CC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
The title compound was prepared by a method similar to Example 130, using (2R)-N-{((3S)-1-cyclopropylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide and cyclopropylmethyl bromide. The compound was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:11]1([CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCCCCOCCc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Product: c1ccc(CCOCCCCCCNCc2ccccc2)cc1

Procedure:
[2-[(6-Bromohexyl)oxy]ethyl]benzene (4.0 g) was added dropwise to benzylamine (20 ml) at 110°. The solution was heated at 110°-120° for 90 min, cooled, and treated with hydrochloric acid (2M; 125 ml). The mixture was extracted with EA (2×100 ml) and the extract was washed with aqueous sodium carbonate (100 ml) and brine (100 ml), dried and evaporated. Distillation of the residue gave the title compound as a colourless oil (3.2 g) b.p. 180°-190°/0.1 mmHg. T.l.c. (CX-ER 1:1) Rf 0.25.
Reaction SMILES: [Si:1]([Cl:5])([Cl:4])([Cl:3])[Cl:2].N.[N:7]#[N+:8][O-].[O:10]=[O+:11][O-:12]>>[Si:1]([Cl:5])([Cl:4])([Cl:3])[Cl:2].[NH3:7].[O:10]=[O+:11][O-:12].[N:7]#[N:8]
Reactant: N#[N+][O-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: N
Agent: O=[O+][O-]
Product: N#N

Procedure:
An SiON passivation layer, e.g., 104 in FIGS. 1A and 1B, can be deposited in MOCVD mode using reactants SiCl4, NH3, N2O, or ozone appropriately diluted in a nitrogen carrier at approximately 650 C˜750 C. Such a layer could also be formed in ALD mode with cycles of SiCl4 at approximately 400 C˜450 C and NH3-N20-N2 or NH3-O3-N2 at approximately 650 C˜700 C while maintaining appropriate gas pressures of SiCl4, NH3, and N2O to achieve desired film composition at a slow deposition rate less than 0.1 nm/sec.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[S:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1.CO>[OH-].[K+].CCO.C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:21](=[CH:32][C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH2:20][CH2:19]3)[N:10]=[CH:9]1
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=C1C(=Cc2ccsc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 62.7 %

Procedure:
According to the method of Example 32, Step 2, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.270 g, 0.76 mmol) was reacted with thiophene-3-carboxaldehyde (0.128 g, 1.14 mmol) in 5 mL of 4% KOH in EtOH for 22 hours to afford, after chromatography (silica gel, 50 g; 8% MeOH in DCM), 0.167 g (59%) of the title compound as a dull yellow powder, mp 94-96° C.: CI-MS m/e 351 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:15]1([CH2:18][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), cyclopropylmethyl bromide (60.0 uL, 0.62 mmol, Aldrich, Cat. No. 242403), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 120 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OCC1C=CC=CC=1)N.O[N:38]1C2C=CC=CC=2N=[N:39]1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:38][NH2:39])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of 19 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 220 ml of dimethylformamide was cooled to 0° C. and was treated in succession with 9.22 g of benzyl carbamate, 8.43 g of 1-hydroxybenzotriazole, 7.05 ml of N-methylmorpholine and 11.7 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was allowed to warm to room temperature and was then stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The ethyl acetate layer was washed with 5% sodium hydrogen carbonate and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the ethyl acetate was evaporated and the residue dissolved 200 ml of methanol and 2.5 g of 10% palladium-on-charcoal added. The mixture was shaken in a hydrogen atmosphere for 4 hours and then the catalyst was removed by filtration. The methanol was evaporated and the residue stirred with hexane and filtered. There was obtained 17.41 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2>C(O)(C)C>[ClH:1].[CH2:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:9]3[C:4]4[CH:3]=[CH:2][CH:11]=[N:10][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: Clc1cnc2ncncc2c1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CC(C)O
Product: Cl
Product: c1cnc2ncnc(Nc3ccc4c(c3)CCC4)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 6-chloropyrido[2,3-d]pyrimidine (1.656 g, 10 mM) and 5-aminoindan (1.332 g, 10 mM) in isopropanol (60 ml) is heated to reflux for about 20 h. The resulting salt suspension is then cooled to room temperature, filtered and the residue washed with ice-cooled isopropanol to give almost pure title compound in about 80% yield.