Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])([CH2:15][CH3:16])[CH3:14]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([N:17]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:5]
Reactant: CCC(C)NC(C)CC
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(C)N(C(=O)c1cc(Cl)cc(Cl)c1Cl)C(C)CC
Temperature: 25 °C

Procedure:
Into a 250 ml flask, provided with a reflux condenser, were introduced 10 g of 2,3,5-trichlorobenzoyl chloride in 20 ml of anhydrous C6H6, a solution of 5.3 g of di-sec.butylamine in 7 ml of anhydrous C6H6 and 5 g of triethylamine. This mass was then heated to reflux temperature for about 1 hour. Thereupon it was left to cool down to room temperature and the solvent was removed under reduced pressure in a rotating evaporator. The mass was then washed with acidulated H2O, with H2O and was then extracted with ethyl ether. The etheric extract was then dried on anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. 12.6 g of yellowing crystals of 2,3,5-trichloro-N,N-di-sec.butyl-benzamide were obtained.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:37])[CH2:36][CH2:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([OH:37])[CH2:34][CH2:35][CH2:36]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 198. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.29 (dd, J=8.7, 4.0 Hz, 1H), 8.14 (t, J=8.8 Hz, 1H), 7.90 (s, 1H), 7.35 (d, J=9.5 Hz, 2H), 5.89 (br, 1H), 4.80 (dd, J=10.5, 3.7 Hz, 1H), 4.32-4.07 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.11-3.00 (m, 1H), 2.50-2.39 (m, 2H), 2.38-2.26 (m, 2H), 2.09-1.88 (m, 2H), 1.84-1.68 (m, 2H), 1.67-1.57 (m, 2H). LCMS (ES+) m/z 534 (M+1).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:12][CH:11]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of Zn powder (4.80 g, 73.5 mmol) and THF (100 mL) under N2 was added TiCl4 (3.9 mL, 35.7 mmol), dropwise. The resulting yellow suspension was stirred at RT for 45 min followed by reflux for 2.5 h. A solution of cycloheptanone (3.42 g, 30.6 mmol) and 4-bromobenzophenone (2.54 g, 9.75 mmol) in THF (40 mL) was added dropwise to the refluxing reaction over 15 min. After 2 h the reaction was cooled to RT and then quenched by sequential dropwise addition of water (75 mL) and 10% aqueous Na2CO3 (75 mL). The mixture was stirred overnight at RT then diluted with EtOAc (300 mL) and filtered through a celite pad. The celite pad was rinsed with EtOAc (250 mL) and the colorless filtrates transferred to a separatory funnel. The organic fraction was washed with brine (300 mL), dried (Na2SO4) and concentrated to 6.50 g of a colorless oil. The oil was purified by column chromatographed on silica gel (150 g) with hexanes followed by 2% EtOAc:hexanes and the product 1 isolated as a colorless oil that solidified on standing (2.54 g, 76%). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 8H), 2.27 (br s, 4H), 7.15-7.39 (m, 7H), 7.55 (d, J=8.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1Cc1ccccc1C2=O
Reactant: [OH-]
Agent: [K+]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 39 %

Procedure:
6.3 g of 4-aminoanthrone are dissolved in 100 ml of hot 1 N KOH. Air is then passed through the solution at 80° C until the yellow exudation from a spot test has disappeared. After filtering off and washing until neutral, 4.5 g of product containing 58.2% of 1-aminoanthraquinone (39% yield) are obtained. On boiling with toluene, which dissolves the 1-aminoanthraquinone, a yellow residue is obtained which according to analysis, NMR-spectrum, IR-spectrum, mass spectrum and molecular weight determination is 4,4' -diamino-dihydrodianthrone (melting point: 251°-253° C).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (568 mg) described in Preparation Example 113 and pyrrolidin-2-one (0.12 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (427 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(O)(=O)C>[Br:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Br:1])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)c(Br)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
6-Bromooxindole (0.168 g, 0.8 mmol) was dissolved in acetic acid (4 mL) and stirred for 5 min at room temperature. N-Bromosuccinimide (0.14 g, 0.8 mmol) was added and the yellow reaction mixture was stirred for 3 h at ambient temperature. The mixture was poured onto ice and the resulting precipitate was collected by filtration and dried in vacuo to give 0.192 g (83% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.61 (s, 1 H), 7.60 (s, 1 H), 7.14 (s, 1 H), 3.52 (s, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate (14) in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen. The residue was then diluted in MTBE and washed once with 1M citric acid (adjusted to pH3). The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo to afford (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15) as a waxy solid that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[I:19]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[OH:1][C:2]1[C:3]([I:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O)ccc3c2)COC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
The mixture of (R)-4-(6-Hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (221.7 mg, 0.0009114 mol), N-iodosuccinimide (226 mg, 0.00100 mol) and zirconium tetrachloride (33 mg, 0.00014 mol) in methylene chloride (16 mL, 0.25 mol) was stirred at room temperature for 3 h. After filtrating through Celite and washing with methylene chloride, the concentrated residue was chromatographed to give (R)-4-(6-hydroxy-5-iodonaphthalen-2-yl)-4-methyloxazolidin-2-one as a light yellow solid (290 mg, 86%). LCMS: Rf=1.33 min (370.07, M+1, 100%). 1H NMR (400 MHz, MeOD) δ=8.10 (d, J=8.9 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.56 (dd, J=2.1, 8.9 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.52 (d, J=8.5 Hz, 1H), 4.43 (d, J=8.5 Hz, 1H), 1.80 (s, 3H).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)=O.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].C(N(CC)CC)C>C(O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[N:4]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
17 mg (1.5 mmol) of thioacetamide is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added, then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol 95/5). After drying, 18 mg (34%) of 8-(2-methyl-thiazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].OS(O)(=O)=O.[C:16]([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: O=C([O-])O
Reactant: Cc1sc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-5-methylthiophene-2-carboxylic acid (45 g, 204 mmol) in methanol (225 mL) was added concentrated H2SO4 (4.0 g, 41 mmol). The reaction mixture was heated to reflux overnight, cooled to room temperature, poured into saturated NaHCO3 (800 mL), and left to stir for 30 min. The precipitate was filtered, washed with water, and dried under high-vacuum to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H); 3.88 (s, 3H); 2.45 (s, 3H). LRMS (APCI) calc'd for (C7H8BrO2S) [M+H]+, 234.9. found 234.9.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]5[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=5)=[O:68])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 77.7 %

Procedure:
The same procedure as in Example 1--1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.39 g, 2.34 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (1.24 g, 2.34 mmol, compound of Reference Example 5-6) to obtain p-nitrobenzyl (IR,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (1.59 g, yield: 77.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXVIII) (8.00 g, 30.4 mmol) was taken in neat oxalyl chloride (20 ml), 0.2 ml of DMF were added and the mixture was stirred at room temperature for 1 hour. The completion of reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. The reaction mixture was concentrated under reduced pressure to provide (R)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXIX) (8.33 g) which was directly used in the next reaction.
Reaction SMILES: [S-]C#N.[NH4+].Cl[C:6]1[C:11]([C:12]([N:14]=[C:15]=[S:16])=[O:13])=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>CC(C)=O.C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([N:22]([C:15]2[S:16][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:13])[N:14]=2)[CH3:23])=[CH:20][CH:19]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=C(N=C=S)c1cnccc1Cl
Agent: N#C[S-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(c1ccc(Cl)cc1)c1nc(=O)c2cnccc2s1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][C:27]#N)[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C[OH:30].O>C1(C)C=CC=CC=1>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@:16]1([CH2:26][CH:27]=[O:30])[CH2:25][C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: N#CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1.0 M DIBAL solution in toluene (3.0 ml, 3 mmol) was added drop-wise to a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (350 mg, 1.4 mmol) in 7 mL toluene at −78° C. The resulting mixture was stirred at −78° C. until completion (1.5 h). The reaction was then quenched with 5 eq of MeOH (0.28 mL) and 0.1 mL water, stir while warming, 175 mg NA2SO4 added, stir at room temp. 2 h to give 310 mg (80%) of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde. LCMS m/z 250.6 (M+1) observed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[Li]CCCC.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].O>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 10 g (42.39 mmol) of 1,3-dibromobenzene in 80 mL of anhydrous Et2O, cooled to −78° C. and maintained under a nitrogen atmosphere, are added dropwise with stirring, over 30 minutes, 26.49 mL (42.39 mmol) of a solution of BuLi (1.5M/hexane). After stirring for a further 30 minutes at −78° C., 5.96 mL (46.63 mmol) of TMSCl are added dropwise to the reaction mixture. Stirring is maintained at this temperature for 90 minutes and the reaction mixture is then hydrolysed by adding 15 mL of water. The product is extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with saturated aqueous NaCl solution (2×25 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude reaction product is purified by chromatography on a column of silica gel, eluting with heptane, to give 9.3 g of the expected 1-bromo-3-trimethylsilylbenzene, in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[CH2:6][OH:7])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(CO)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)1-butyl}-aminocarbonylmethyl}-benzoate by reduction with lithium borohydride in boiling tetrahydrofuran in the presence of 10% of trimethyl borate.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O:46][P:47](=[O:74])([O:71]CC)[O:48][CH2:49][C@@H:50]([N:56]([S:61]([C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:8])[NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]([N:56]([S:61]([C:64]1[CH:65]=[CH:66][C:67]([NH2:70])=[CH:68][CH:69]=1)(=[O:62])=[O:63])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:49][O:48][P:47]([OH:71])([OH:46])=[O:74])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(=O)(OCC)OC[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 139.6 %

Procedure:
(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1, step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of (2S)-phosphoric acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (IX) (example 3, step B) and the mixture stirred for 3 h. 20 g of Amberlite XAD-2 resin was then added and the beads were left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly with distilled water (400 mL) and 200 mL of 1M NaHCO3. The beads were then washed with 4×50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to yield 2.4 g (83%) of white solid after evaporation.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](F)[C:6]=1[S:16][CH3:17].O>O1CCCC1>[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:2][CH3:1])[C:6]=1[S:16][CH3:17]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)c(SC)c1F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(SC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Sodium methoxide (5.6 g) was added to a solution of methyl 4-chloro-2-fluoro-3-(methylsulphenyl)benzoate (85% pure, 19.2 g) in dry tetrahydrofuran and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-methoxy-3-(methylsulphenyl)benzoate (17.1 g) as a yellow oil NMR (CDCl3) 2.5(s,3H), 3.95(s,3H), 4.0(s,3H), 7.25(d,1H), 7.65(d, 1H) contaminated with 15% methyl 4-chloro-3-(chloromethylsulphenyl)-2-methoxybenzoate (determined by the ratio of NMR signals).