Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[Cl:12][CH2:13][C:14]#[N:15]>Cl.C1(OC)CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:15][C:14]([CH2:13][Cl:12])=[N:1][C:2]=2[CH:6]=1
Reactant: N#CCCl
Reactant: COC(=O)c1sc(Br)cc1N
Agent: Cl
Solvent: COC1CCCC1
Product: O=c1[nH]c(CCl)nc2cc(Br)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (15 g) produced in Example 1, step C, chloroacetonitrile (12 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (100 mL) was stirred at room temperature for 2 hr, and stirred at 70° C. for 1 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained solid was dried at 80° C. for 8 hr under reduced pressure to give the title compound (18 g) as a pale-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.C(O)(C)C.O1CCCC1.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Brc1ccc2cc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Bromoanthraquinone 10 (8.50 g, 0.0296 mol, 1 equiv) and a 50:50 mixture of isopropyl alcohol and tetrahydrofuran (200 mL) were stirred for 10 minutes at 0° C. forming a yellow suspension. NaBH4 (6.70 g, 0.177 mol, 6.0 equiv.) was added to the suspension at 0° C. The mixture was stirred at 0° C. for three hours, turning red in color. The solution was then warmed to room temperature. Additional NaBH4 (3.35 g, 0.089 mol, 3.0 equiv.) was added to the solution at room temperature and the solution was stirred at room temperature for 12 hours, turning into an orange suspension. Deionized water (10 mL) was added to the solution at room temperature and the solution was stirred at room temperature for an additional 12 hours. The consumption of 2-bromoanthraquinone 10 was monitored by thin-layer chromatography (35% CHCl3/hexane, Rf=0.33). Once the consumption of 2-bromoanthraquinone 10 stopped entirely (it was never fully consumed), the volatiles were removed by rotary evaporation. 3 M HCl was slowly added to the solution until bubbling ceased, then additional 3 M HCl (30 mL) was added. The solution was heated at reflux for 6 hours, turning into an opaque, yellow suspension in the process. The mixture was cooled to room temperature, turning into a transparent solution containing yellow-brown crystals. The contents underwent rotary evaporation as much water as possible. The contents were then vacuum-filtered and washed using deionized water to remove any water, acid and ionic salt, leaving behind a yellow-brown colored solid. The vacuum-filtration receiving flask was changed and the solid was washed with CH2Cl2 through the filter paper. The CH2Cl2 was removed through rotary evaporation. The remaining solid was purified through column chromatography (100% hexane, Rf=0.27), providing 2-bromoanthracene 11 as a white, powdery solid (2.00 g, 26%). 1H NMR (CDCl3): δ 8.42 (s, 1H), 8.34 (s, 1H), 8.18 (d, 1H), 8.01 (m, 2H), 7.87 (d, 1H), 7.50 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH2:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 103.8 %

Procedure:
N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline tert-butyl ester (905 g) was dissolved in ethanol (4 liters) and 10% palladium on carbon (20 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 12 hours and then the catalyst was removed by filtration through through diatomaceous earth. The filtrate was concentrated under vacuum and the residue twice re-evaporated from toluene (1 liter) to give L-Valyl-L-Proline tert-butyl ester as an oil (628 g); TLC, Rf =0.2, acetone:hexane (20:80); MS: m/z=271(M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>CCOCC>[ClH:18].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:7]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(Cl)cc3)c3cc(F)ccc23)CC1
Product: Cl
Temperature: 100 °C

Procedure:
A mixture of 2.0 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole and 5 ml of 4-chlorobenzoyl chloride was heated at 100° C. in a steam bath for 2 hrs. After cooling, ether was added and the solid was collected. The solid was combined with a 2.5 g sample from another experiment and recrystallized twice from ethanol-ether to yield 4.7 g (56%, calculated on the combination of both experiments) of product, mp 258°-260° C.
Reaction SMILES: C(NCC)C.[Li]CCCC.[Br:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17].CN([CH:21]=[O:22])C>C1COCC1.CCCCCC>[Br:11][C:12]1[S:13][C:14]([CH:21]=[O:22])=[CH:15][C:16]=1[CH3:17]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCNCC
Product: Cc1cc(C=O)sc1Br
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added at −40° C. under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane. After addition, the solution was stirred at −40° C. under nitrogen for 30 minutes, cooled to −78° C. and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at −78° C. for 30 minutes and treated with anhydrous DMF (100 mL). The mixture was allowed to warm to ambient temperature and was quenched with 1N aqueous hydrochloride solution (1L). The solution was extracted with ethyl acetate (3×450 mL) and the extracts washed with water, brine and dried (MgSO4). After removal of solvent in vacuo, the title compound was obtained as a white solid (46 g, 88.3%). A sample of the product was crystallized from hexane: mp 63-65° C.; IR (KBr) 1654 cm−1. 1H-NMR (CDCl3) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206 (M+). Anal. Calc. For C6H5BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCCBr)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
2a, 3,4,5-Tetrahydrobenz [cd]indole-2(1H) -one (1.0 g, 5.8 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 ml). Thereto was added sodium hydride (250 mg, 6.3 mmol), and the resulting solution was stirred at a room temperature for 1 hour. The reaction solution was mixed with 1,5-dibromopentane (2.4 ml, 17 mmol) and again stirred for 17 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 230 mg of the title compound (0.70 mmol, 12% in yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=N1.[CH2:22](O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([CH2:12][N:17]2[CH:22]=[CH:19][N:20]=[CH:21]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(C=Cc2ccc(Cl)cc2)CO1
Product: CC(C)(C)C(O)(C=Cc1ccc(Cl)cc1)Cn1ccnc1
Yield: 77 %

Procedure:
A solution of 17.75 g (0.075 mole) of 2-(4-chlorophenyl-ethenyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mole) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction mixture was then concentrated and the crystalline residue was stirred with ether. The solid was then filtered off and recrystallised from acetonitrile. 17.7 g (77% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(imidazol-1-yl-methyl)-1-penten-3-ol of melting point 139°-41° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31](F)=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncccn4)CC3)CC2)n1
Temperature: 110 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (10 mg, 0.036 mmol) and cesium carbonate (35 mg, 0.11 mmol) were stirred in NMP (2 ml) and 2-chloro-5-fluoropyrimidine (8.2 mg, 0.72 mmol) was added. The mixture was heated at 110° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41].C(=O)([O-])O.[Na+]>ClCCl.O>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])=[O:41]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC2CN(C(=O)OCc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1OC
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a mixed solution of 1-(benzyloxycarbonyl)-3-(2,3-dimethoxybenzyl)piperazine (0.65 g) and triethylamine (0.293 ml) in dichloromethane (17 ml) was added dropwise a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.534 g) in dichloromethane (2.5 ml) under ice-cooling. After being stirred at the same temperature for 2 hours, the reaction mixture was poured into a mixed solvent of water (40 ml) and dichloromethane (25 ml) and the whole was adjusted to pH 9 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of n-hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-(2,3-dimethoxybenzyl)piperazine (0.84 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)cc2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (534 mg, 1.9 mmol) and 4-hydroxy-benzohydrazide (304 mg, 2.0 mmol) were coupled similarly to the procedure described for the preparation of intermediate 1b. After column chromatography (3% methanol/EtOAc) the title compound was isolated as a white solid (490 mg, 61%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.76 (br s, 1H), 9.49 (br s, 1H), 9.15 (br s, 1H), 7.83 (AA′XX′, =8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 6.89 (AA′XX′, J=8.8 Hz, 2H), 6.64 (d, J=8.7 Hz, 1H), 5.53 (d, J=7.2 Hz, 1H), 5.01 (br s, 1H), 4.39 (m, 1H), 4.11 (dd, J=3.0, 6.4 Hz, 1H), 2.33 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl.[NH2:26][C@@H:27]([CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)CC)(C)C>C1COCC1>[C:31]([O:30][C:28](=[O:29])[C@@H:27]([NH:26][C:13]([O:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2)=[O:14])[CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:33])([CH3:34])[CH3:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)OC(C)(C)C
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A solution of 10.9 g (65.4 mmol) of (1-hydroxymethyl)adamantane and 10.6 g (65.4 mmol) of carbonyldiimidazole in 60 ml of THF were stirred at 50° C. for 1.5 h. 9.7 g (32.7 mmol) of tert-butyl (S)-2-amino-3-tert-butoxycarbonylaminopropionate hydrochloride in 25 ml of THF and 5.6 ml (32.7 mmol) of diisopropylethylamine were added, and the mixture was stirred at 60° C. for 4 h and allowed to stand at room temperature overnight. The solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (7/3). 8.7 g (59%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:16].[CH2:17](OS([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC=O)=O>O>[S:16]1[C:3]2[CH:4]=[CH:5][C:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[N:1]=[CH:17]1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Nc1c(S)ccc2c1ccc1ccccc12
Agent: O=COC=O
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ccc1c2ccc2scnc21
Yield: 69 %

Procedure:
5 mmol of 1-amino phenanthren-2-thiol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of formic anhydride was added for 5 minutes. A precipitation product was obtained in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain phenanthrothiazole at a yield of 69%.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][C:10]([O-:12])=[O:11].[Na+]>C1COCC1.CS(C)=O>[CH:1]1([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: O=C([O-])CCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)COC1CCCCC1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of cyclohexanol (1.75 g, 17.5 mmol) in THF was added, and the mixture was warmed to 25° C. for 1 hour. The THF was removed by distillation under vacuum, and a solution of sodium chloroacetate (2.5 g, 22 mmol) in DMSO (50 ml) was added. The reaction mixture was treated as in Example 3 and 2.3 g of product (83% yield) was obtained as a colorless oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[I:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)[C:28]([C:41](O)=[O:42])=[CH:27]2.[NH2:44][C:45]1[CH:46]=[N:47][C:48]([N:51]2[CH2:54][CH2:53][CH2:52]2)=[CH:49][CH:50]=1>CN(C=O)C.C(OCC)(=O)C.O>[N:51]1([C:48]2[N:47]=[CH:46][C:45]([NH:44][C:41]([C:28]3[N:29]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)[C:30]4[C:26]([CH:27]=3)=[CH:25][C:24]([I:23])=[CH:32][CH:31]=4)=[O:42])=[CH:50][CH:49]=2)[CH2:54][CH2:53][CH2:52]1
Reactant: O=C(O)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
0.29 g (1.52 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 0.2 g (1.52 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 0.6 g (1.52 mmol) of 5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 8.2, in 15 ml of DMF. The reaction mixture is stirred at ambient temperature for 20 minutes. 0.25 g (1.67 mmol) of 3-amino-6-(azetidin-1-yl)pyridine, prepared according to the protocol described in stage 1.6, is subsequently added to the reaction mixture. After stirring at 20° C. for 18 hours, the reaction mixture is poured into a mixture of 50 ml of water and 50 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The isolated product is subsequently precipitated, then washed with isopropyl ether at reflux, filtered under hot conditions, and then dried under reduced pressure. 0.47 g of the expected product is thus isolated.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6].C1CCC(NC2CCCCC2)CC1.S(=O)(=O)(O)O.[F:34][C:35]1[C:40](O)=[C:39]([F:42])[C:38]([F:43])=[C:37]([F:44])[C:36]=1[F:45].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.O1CCOCC1.CCOCC>[F:34][C:35]1[C:40]([O:6][C:5](=[O:7])[C@H:4]([CH2:3][CH2:2][CH3:1])[NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[C:39]([F:42])[C:38]([F:43])=[C:37]([F:44])[C:36]=1[F:45]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8.0 g (20 mmoles) of BOC--Nva--OH.DCHA are added to a mixture of 60 ml of ether and 20 ml of 2 n aqueous sulfuric acid, and the mixture is shaken until dissolution is complete. The etheral solution is separated, washed with 20 ml of 2 n aqueous sulfuric acid and water, dried, and evaporated in vacuo. The oily residue and 3.70 g (20 mmoles) of pentafluorophenol are dissolved in 25 ml of ethyl acetate, the solution is cooled to 0° C., 3.92 g (19 mmoles) of DCC are added, and the reaction is conducted for one hour. Thereafter the suspension is filtered, the filtrate is evaporated in vacuo, and the oily residue is dissolved in 50 ml of n-hexane. The solution is washed with 5×20 ml of 5% aqueous sodium bicarbonate solution and 2×20 ml of water and evaporated in vacuo. The oily residue solidified upon cooling. 6.21 g (81%) of BOC--Nva--OPFP are obtained; m.p.: 60°-62° C., Rf3 =0.70, [α]D :-32.3° C. (c=1.0, in dioxane).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20].[CH2:21]([Li])CCC.C(OC)=O.Cl>O1CCCC1>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[CH:21]=[C:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: [Li]CCCC
Reactant: COc1ccc(SCc2c(F)cccc2F)c(Cl)c1Cl
Agent: Cl
Solvent: COC=O
Solvent: C1CCOC1
Product: COc1cc2cc(-c3c(F)cccc3F)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 15 g of (2,3-dichloro-4-methoxyphenyl)(2',6'-difluorobenzyl)sulfide in 140 ml of dry tetrahydrofuran at -75° is added dropwise 25 ml of 2.2M n-butyllithium over a period of 20 mins, maintaining the temperature below -65°. After stirring at this temperature for 1 hr, 10 ml of dried methyl formate is added dropwise, maintaining the temperature below -60°. The reaction mixture is poured onto 100 ml of 10N hydrochloric acid. The mixture is extracted with ethyl ether. The ether extract is dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. The oil is heated to 120° and 240 g of warm polyphosphoric acid is added. The reaction mixture is warmed at 130° for 20 mins. The mixture is allowed to cool and to the mixture is added 400 ml of ice water. The aqueous solution is extracted with ethyl ether. The ether extract is washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. Crystallization from hexane, followed by recrystallization from acetone-hexane, gives 7 g of 6,7-dichloro-2-(2',6'-difluorophenyl)-5-methoxybenzo[b]thiophene.