Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([SH:9])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([S:9][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[S:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: CCCCCCCCCCCCCCCCCCBr
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCSP(=S)(C1CCCCC1)C1CCCCC1
Yield: 77.8 %

Procedure:
To 14.0 g. (0.05 m.) of the ammonium salt of dicyclohexylphosphinodithioic acid in 250 mls. of acetone was added 16.67 g. (0.05 m.) of n-octadecylbromide and the mixture was refluxed for 15 hours. The precipitate was then separated by filtration and the filtrate was cooled to precipitate a crystalline solid. The crystalline material was filtered off and recrystallized from acetone to obtain 20 g. (77.8% yield) of product which melted at 67°-69° C.
Reaction SMILES: [CH2:1]([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH2:1]([S:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCSCCCCCCl
Solvent: ClCCl
Product: CC(C)CCS(=O)CCCCCCl
Temperature: -20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Dissolve 5-chloropentyl isopentyl sulfide (1.0 g, 5.39 mmol) in methylene chloride (25 mL), place under nitrogen atmosphere and cool to -20° C. Add, by dropwise addition, a solution of meta-chloroperbenzoic acid (930 mg, 5.39 mmol) in methylene chloride (25 mL). Stir overnight at room temperature. Add additional meta-chloroperbenzoic acid (930 mg). Stir briefly and filter. Treat with aqueous sodium metabisulfite (until negative starch-iodide test) and separate the layers. Wash the organic phase with saturated sodium hydrogen carbonate until basic and dry (MgSO4). Evaporate the solvent in vacuo to yield a yellow oil. Purify by silica gel chromatography (50% ethyl acetate/hexane) to yield 750 mg of 5-chloropentyl isopentyl sulfoxide as a clear oil; MS (CI/CH4) m/z 225(M+1), 189 (M+1-HCl).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:28]([CH3:30])[CH3:29])=[N:7][C:8]([CH:25]([CH3:27])[CH3:26])=[C:9]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:28]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[C:8]([CH:25]([CH3:27])[CH3:26])[N:7]=1)([CH3:30])[CH3:29]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CN2CCOCC2)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(C)C)c(CN2CCOCC2)c(-c2ccc(F)cc2)c1CO
Yield: 84 %

Procedure:
The intermediate obtained in Step A (375 mg, 0.905 mmol) was dissolved in dry THF (50 mL), treated dropwise with lithium aluminum hydride (1M/THF, 1.81 mL) and the reaction stirred at reflux for 24 hours. The reaction was quenched by the successive dropwise addition of water (0.1 ml), NaOH 20% (0.1 ml), and water again (0.3 ml). Concentration in vacuo afforded a white residue which was partitioned between CH2Cl2 and water. The organic layer was dried with MgSO4, filtered, and concentrated to afford an oil. The product was passed through a pad of silica (40% diethyl ether/hexanes) yielding an oil which slowly solidified to give the title compound as a white solid (295 mg, 0.76 mmol, 84%). 1H NMR (300 MHz, CDCl3): δ 7.14 (m, 4 H), 4.35 (d, 2 H), 3.53 (t, J=4.8 Hz, 4 H), 3.45 (m, 2 H), 3.18 (s, 2 H), 2.18 (t, J=4.5 Hz, 4 H), 1.26 (m, 13 H); FAB-MS calcd for (C23H31N2FO2) 386, found 387 (M+H). Anal. Calcd for C23H31N2O2F: C, 71.47; H, 8.08; N, 7.25; F, 4.92 Found: C, 71.55; H, 8.16; N, 7.05; F, 4.70. mp 93.5-95.5° C. Rf=0.4 (40% diethyl ether/hexane).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[C:53]([Cl:62])[C:52]=2[Cl:63])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[C:53]([Cl:62])[C:52]=2[Cl:63])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:31][CH:32]=2)[CH2:9][NH:8][CH2:15]3)=[O:25])[CH2:48][CH2:47]1
Reactant: COCCCc1cc(Cl)c(Cl)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCCc1cc(Cl)c(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 733.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([S-:6])=[S:5])[CH3:2].[K+].[PH:8](=[O:11])([OH:10])[OH:9].[CH2:12]([C:14]([CH2:42][CH3:43])([CH:16](Br)[C:17]1[N:21]=[CH:20][N:19]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:15])[CH3:13].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[PH:8](=[O:9])([OH:11])[OH:10].[CH2:42]([C:14]([CH2:12][CH3:13])([CH:16]([S:5][C:4]([O:3][CH2:1][CH3:2])=[S:6])[C:17]1[N:21]=[CH:20][N:19]([C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:15])[CH3:43]
Reactant: CCOC(=S)[S-]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=S)SC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(C)(CC)CC
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A stirred solution of 18-Crown-6 (0.03 g) in dry tetrahydrofuran (25 ml) was treated successively with potassium ethylxanthate (0.44 g) and diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29). The mixture was allowed to stand for two days, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3(ethoxythiocarbonylthio)-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.86 g) as a colourless gum. NMR(CDCl3): δ1.25(6H,m), 1.4(3H,t), 1.7-1.9(2H,m), 2.3-2.4(2H,m), 4.0(4H,m), 4.6(2H,m), 5.05(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,S). M/S: M+ 609.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23](=[O:25])[CH3:24])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Product: CC(=O)n1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Yield: 86 %

Procedure:
Using the procedure of example 66, compound 13 (24 mg) and acetic anhydride (7.7 μL) were used to provide compound 68 (24 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 8.85 (d, 1 H), 8.52 (d, 1 H), 8.40 (d, 1 H), 8.28 (d, 1 H), 7.35 (dd, 1 H), 6.90 (d, 1 H), 5.15 (m, 1 H), 3.92 (m, 1 H), 2.15 (m, 2 H), 1.85 (m, 2 H), 1.70 (m, 2 H), 1.50 (m, 2 H), 1.30 (m, 2 H). MS (ESI) m/z: 336 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[H][H]>C(O)(=O)C.[Pt].[C]>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2
Reactant: Cc1ccc2c(Cl)c(Cl)ccc2n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(Cl)c2Cl)N1
Yield: 78.5 %

Procedure:
5,6-Dichloroquinaldine (5.5 g) was dissolved in 50 ml of acetic acid and 0.1 g of 5% platinum-carbon was added to the solution, which was then subjected to Parr's hydrogenation method to reduce the compound catalytically at a hydrogen gas pressure of 4 kg/cm2. After theoretical amount of hydrogen was absorbed the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After rendering it alkaline with 50 ml of water and 20% sodium hydroxide, the residue was extracted with 100 ml of chloroform. The extract was dried by the addition of anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:19])=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:24][CH:25]=2)=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CCCl
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1

Procedure:
By essentially following the procedure outlined in Example 3, part D, the title compound was prepared from 4-hydroxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone (Example 28, Part A) and 2-diethylaminoethyl chloride in 86% yield. Flash chromatography [SiO2; gradient 1-4% of (1:1 TEA-MeOH) in EtOAc] gave the desired compound as a light oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13]I>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+].[Ag+]>[CH3:13][O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: CCOC(=O)c1ccnc(O)c1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccnc(OC)c1
Yield: 86 %

Procedure:
A mixture of ethyl 2-hydroxy-pyridine-4-carboxylate (1.0 g, 6 mmol), (Chem. Abs. 1957, 8740c), methyl iodide (1 ml) and silver(I)carbonate (1.64 g) in toluene (20 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the insolubles removed by filtration through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was washed with water, dried (MgSO4) and the solvent removed by evaporation to give ethyl 2-methoxy-pyridine-4-carboxylate (0.93 g, 86%) as a yellow oil. 1H NMR Spectrum: (CDCl3) 1.30(t, 3H); 3.90(s, 3H); 4.30(q, 2H); 7.24(s, 1H); 7.35(d, 1H); 8.20(d, 1H) MS-ESI: 182 [MH]+
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:34]2[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:36][CH2:35]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Product: COc1ccc(CCN2CCN(C(=O)c3ccc(N(CCOC(C)C)C(=O)CCl)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.88 g of [2-(4-methoxyphenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-methoxyphenyl)ethyl]piperazine. The hydrochloride thereof melts at 139°-140°.
Reaction SMILES: [C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[N:11]=[N:10][C:9](Cl)=[CH:8][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[NH2:22][NH2:23]>C(O)C>[C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[N:11]=[N:10][C:9]([NH:22][NH2:23])=[CH:8][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C1CCc2nnc(NN)cc2C1
Reaction time: 23 h

Procedure:
A suspension of 13.8 g of 6-tert.butyl-3-chloro-5,6,7,8-tetrahydrocinnoline in 100 cc of hydrazine hydrate is stirred in an oil bath of 100° for 23 hours, whereby 20 cc of tetrahydrofuran are added after 1 hour. The mixture is worked up as described in Example 4, and the resulting crude oily title compound is dissolved in 40 cc of absolute ethanol, and hydrochloric acid in ethanol is added to the solution until an acid reaction is obtained. The hydrochloride which crystallizes is triturated with 100 cc of concentrated ammonia, the insoluble title compound is filtered off and has a
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[NH:36]1[CH2:39][CH2:38][CH2:37]1.[CH:40]([OH:42])=[O:41].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:40]([OH:42])=[O:41].[N:36]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[N:19]=[C:18]([C:28]([N:30]4[CH2:34][C:33](=[O:35])[NH:32][CH2:31]4)=[O:29])[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: C1CNC1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCCN4CCC4)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and azetidine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 13 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Reactant: Nc1ccc(F)cc1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4ccc(F)cc4)cc3c2C1
Yield: 7.1 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol 4-fluoroaniline, 0.001 gm (7%) of the title compound were recovered.
Reaction SMILES: Cl.C(OC([O:7][CH:8]([CH:17]1[CH2:22][CH2:21][C:20]([N:29]([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)C.[OH-].[Na+]>CC(C)=O>[CH3:30][N:29]([CH3:31])[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:22][CH:17]([CH:8]([OH:7])[CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH2:19]1
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)C1(c2ccccc2)CCC(C(O)COc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 M hydrochloric acid (10 ml) was added to a solution of {4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]-1-phenylcyclohexyl}dimethylamine (892 mg, 2.16 mmol) in acetone (30 ml) and the mixture was stirred at room temperature overnight. The pH of the mixture was then rendered alkaline with 0.5 M sodium hydroxide solution and the mixture was subsequently extracted with methylene chloride (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The crude product (1.26 g) was purified by flash chromatography with ethyl acetate/methanol (9:1→0:1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:12]([N:11]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)O
Reactant: CCCCCNCCCCC
Product: CCCCCN(CCCCC)CCC(=O)O
Yield: 95 %

Procedure:
After completion of the reaction, acrylic acid and di-n-pentylamine were assayed by gas chromatography. As a result, formation of 69.2 g (yield 95%) of N,N-di-n-pentyl-β-alanine was confirmed, with the rates of conversion of acrylic acid and di-n-pentylamine being 95% and 95%, respectively.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10]Br.[CH3:12][Si:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Br:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:20]1([C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:28])([CH3:12])[CH3:29])[C:19]1=[O:27])[CH2:10]2
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: BrCc1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(Br)cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-bromobenzene (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (31.5 g, 119 mmol, described in Intermediate 4) in MeOH (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=445 (M+1).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12](=[S:14])=[S:13]>N1C=CC=CC=1>[C:2]1([C:1]2[S:8][S:14][C:12](=[S:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: S=c1nc(-c2ccccc2)ss1
Temperature: -10 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
A solution of thiobenzamide (100 g, 0.74 mol, Alfa Aesar, Ward Hill, Mass.) was added dropwise to a stirred suspension of NaH (22 g, 0.74 mol, 60% suspension in mineral oil) in pyridine (1 L) at −15° C. followed by the addition of carbon disulfide (122 g, 1.6 mol). The reaction mixture was stirred for 3 h at −10° C. and the solvent was evaporated. The residue was treated with ether, the solution was removed, and the insoluble material was treated in water (1 L). The precipitate was filtered off, and the clear solution was cooled to 0-4° C. and acidified with dilute hydrochloric acid. The crystalline precipitate was collected, washed with water, and dried to yield compound 7 (37.5 g, 24%).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[S:9][C:10]([C:13]([O:15][Si](C)(C)C)=[CH2:14])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C@@H:26]1[C@@H:29]([C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH3:31])[C:28](=O)[NH:27]1)(=O)C>>[Si:33]([O:32][C@@H:30]([C@@H:29]1[C@@H:28]([CH2:15][C:13]([C:10]2[S:9][C:8]([CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:20])[CH3:21])=[CH:12][CH:11]=2)=[O:14])[NH:27][C:26]1=[O:25])[CH3:31])([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:35])[CH3:34]
Reactant: C=C(O[Si](C)(C)C)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1

Procedure:
In the same manner as reference example 3, from tert-butyl(dimethyl)[(5-{1-[(trimethylsilyl)oxy]vinyl}thien-2-yl)methoxy]silane prepared in the above step and (2R,3R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxo-2-azetidinyl acetate (20.99 g), there was obtained (3S,4R)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl) thien-2-yl]-2-oxoethyl}azetidin-2-one (10.32 g).
Reaction SMILES: C([O:9][C@H:10]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11]1)(=O)C1C=CC=CC=1.[Li+].[OH-]>CO>[C:14]1([C@H:12]2[CH2:11][C@H:10]([OH:9])[CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O[C@H]1C[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of trans-3-phenylcyclobutyl benzoate (step 1, 6.5 g, 26.0 mmol) in methanol (100 mL) was added 4N aqueous LiOH (20 mL, 80 mmol) and the resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (5:1) to afford 3.65 g (93%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.34–7.16 (5H, m), 4.60–4.51 (1H, m), 3.69–3.59 (1H, m), 2.55–2.37 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11].C(Cl)(=O)[C:18](Cl)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:16]=[C:18]=[O:19])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([Cl:12])[Cl:11]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C=Nc1cc(Cl)c(OC(F)(F)C(Cl)Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
3,5-Dichloro-4-(2,2-dichloro-1,1-difluoroethoxy)benzenamine (12 g, 0.04 mole) was added to a solution of 20 g oxalyl chloride in 100 ml CCl4 and heated under reflux with stirring for 0.5 hour. A solid precipitated. The carbon tetrachloride and excess oxalyl chloride were removed by evaporation in a rotary evaporator. The residue (16 g) was a slightly oily white solid, which was used in the next reaction without purification.