Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([CH:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:36])[C:33]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[S:9])[O:8][C:4]=3[CH:3]=2)=[O:34])[CH2:30][CH2:31]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=S)oc2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc2[nH]c(=S)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a stirred solution of 0.3 g (1.8 mmol) of 6-amino-3H-benzoxazole-2-thione [J. Org. Chem., 19; 758. (1954)] and 0.6 ml (4.3 mmol) of triethylamine in 20 ml of chloroform 0.5 g (1.8 mmol) of (4-benzyl-piperidine-1-yl)-oxo-acetyl chloride (Example 38c) in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.46 g (61.9%) of the title compound. Melting Point: 203° C. (isopropanol)
Reaction SMILES: B(F)(F)F.[CH:5]([C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=1[CH3:17])=[O:6].[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:6][CH:5]([C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=1[CH3:17])[CH2:20][CH:19]=[CH2:18]
Reactant: C=CC[Si](C)(C)C
Reactant: CCOC(=O)c1noc(C=O)c1C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(O)c1onc(C(=O)OCC)c1C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of boron trifluoride diethyletherate (54.1 μl, 0.427 mmoL) in DCM (0.3 mL) was cooled to −78° C. In a separate flask a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (68 mg, 0.371 mmol) and allyltrimethylsilane (59.0 μl, 0.371 mmol) in DCM were cooled to −78° C. and this solution was added dropwise to the boron trifluoride diethyletherate solution. The reaction mixture was stirred at −78° C. for 1 hour and at room temperature overnight. To the resulting mixture was added a saturated solution of NaHCO3 (aq) (5 mL) and this was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the eluent was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-50% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)[N:42]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:44]=1>O1CCOCC1>[C:45]([C:43]1[CH:44]=[C:40]([NH:39][C:38](=[O:37])[NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@@H:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH:14]=3)[CH2:4][CH2:3]2)[N:41]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)[N:42]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: COCC(=O)Nc1cc(O[C@H]2CC[C@H](N)c3ccccc32)ccn1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCC(=O)Nc1cc(O[C@H]2CC[C@H](NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc32)ccn1
Temperature: 80 °C

Procedure:
To a solution of Intermediate 10d (204 mg, 0.62 mmol) and DIPEA (0.127 mL, 0.80 mmol) in 1,4-dioxane (6 mL), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 315 mg, 0.78 mmol) was added. The mixture was heated at 80° C. under argon for 17 h, and then evaporated to dryness. The residue was purified by FCC, eluting with 0-100% ethyl acetate in cyclohexane, to give the slightly impure product (0.262 g). Further purification by HPLC (Method 6) gave the title compound as a white solid (102 mg, 28%). LCMS (Method 5): Rt 4.51 min, m/z 583 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.69-1.81 (1H, m), 1.90-2.24 (3H, m), 2.36 (3H, s), 3.36 (3H, s), 4.05 (2H, s), 4.86-4.94 (1H, m), 5.62-5.67 (1H, m), 6.32 (1H, s), 6.91 (1H, dd, J 2.5, 5.9), 7.03 (1H, d, J 8.4), 7.26-7.37 (8H, m), 7.60 (1H, br d, J 2.0), 8.01 (1H, s), 8.16 (1H, d, J 5.7), 9.90 (1H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[C:11](=[O:36])[NH:10][C:9]1=[O:37].[CH2:38]([O:45][CH2:46]Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:38]([O:45][CH2:46][N:10]1[C:11](=[O:36])[C:12]2[N:13]([C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:37])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(COCc2ccccc2)c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1.3 g (9.44 mmol) of potassium carbonate were added at 60° C. to a solution of 2.4 g (5.9 mmol) of 3-methyl-7-tritylxanthine from stage a) in 50 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.06 ml (7.67 mmol) of benzyloxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 7 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (3/2).
Reaction SMILES: [CH2:1]([NH:3][C:4](=O)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[S:8])[CH3:2].P(Cl)(Cl)(Cl)=O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH2:1]([NH:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:5]=1)[CH3:2]
Reactant: CCNC(=O)CNC(=S)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a dry 1 L round bottom flask equipped with mechanical stirrer, addition funnel and reflux condenser was charged N-ethyl-2-(pyridine-3-carbothioamido)acetamide (50.0 g, 224 mmol) and acetonitrile (400 mL). To this mixture was added phosphorus oxychloride (103 g, 672 mmol) dropwise, and the reaction stirred at ambient temperature for 20 minutes. The reaction mixture was heated to 55° C. and the course of the reaction was monitored by HPLC (YMC AQ column 5% acetonitrile (“ACN”) 95% water-0.05% trifluoroacetic acid (“TFA”) to 95% ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min). After 2 hours, the reaction was essentially complete. The reaction was cooled to 25° C. and the solvent removed by rotary evaporation to give a thick yellow syrup. The thick yellow syrup was carefully poured into saturated aqueous sodium bicarbonate solution (1.5 L) with rapid stirring. The pH of the resulting yellow solution was adjusted with solid sodium bicarbonate until slightly basic (pH=8), and a yellow solid precipitated from solution. Additional cold water (1 L) was added to the mixture and stirred for an additional 20 minutes. The precipitate was collected by vacuum filtration, and rinsed with water (1 L) and hexanes (500 mL). The collected solid was dried in vacuo at 40° C. for 16 hours to give N-ethyl-2-(pyridin-3-yl)thiazol-5-amine as a yellow solid (36.7 g, 80%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.98 (dd, J=2.3, 0.8 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.07 (ddd, J=8.0, 2.3, 1.6 Hz, 1H), 7.31 (ddd, J=8.0, 4.8, 0.8 Hz, 2H), 6.98 (s, 1H), 3.96 (s, 1H), 3.24 (q, J=5.8 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 152.00, 149.21, 149.21, 146.61, 132.17, 130.44, 123.62, 121.84, 43.09, 14.80. Anal. Calc'd. for C10H11N3S: C, 58.51; H, 5.40; N, 20.47. Found: C, 58.34: H, 5.40; N, 20.38; ESIMS m/z 205 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[NH:16][CH:14]([CH3:15])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)NC(C)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
At 0° C., methyl chloroformate (0.67 g, 7.1 mmol) was added dropwise to a mixture of 2-(3-chloro-phenyl)-1-methyl-ethylamine (1.0 g, 5.9 mmol) and potassium carbonate (1.63 g, 11.8 mmol) in THF (20 mL). After the addition, the mixture was stirred at room temperature overnight. After filtration and evaporation of the volatiles, the crude product was purified by flash column chromatography (silica gel, 12 g, 50% hexane in dichloromethane) to give the title compound as a white solid (1.2 g, 90%). MS: 228.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.COC(=O)C(C)(C)CC1N(CC2C=CC(Cl)=CC=2)C2C(C=1SC(C)(C)C)=CC(OC)=CC=2.[Na]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1
Agent: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Product: CC(C)(Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared using the conditions described in Step B of Example 1, but substituting the ester from Step D for the ester of Example 1, Step A. Anal. C, H, N for sodium salt 11/2 H2O Calc. C 65.75; H 5.33; N 5.11 Found. C 66.08; H 5.31; N 5.08.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[C:7]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:8]3[C:13](=[CH:14][C:4]=2[O:3]1)[CH:12]=[CH:11][CH:10]=[CH:9]3.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[S:27]1(=[O:37])=[O:36]>>[O:36]=[S:27]1(=[O:37])[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[C:30](=[O:31])[N:26]1[CH2:25][CH2:24][CH2:23][CH2:22][N:18]1[CH2:19][CH2:20][CH:15]([C:7]2[C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH2:16][CH2:17]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: O=c1[nH]c2c(C3CCNCC3)c3ccccc3cc2o1
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCC(c2c3ccccc3cc3oc(=O)[nH]c23)CC1

Procedure:
From the hydrochloride salt of 4-(2-oxonaphth[2,3-d]oxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid, HC1 salt: 1H NMR (400 MHz, CD3OD) 8.11 (td, J=6.5, 0.9 Hz, 2H), 8.02-7.94 (m, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.68 (d, J=5.3 Hz, 2H), 7.50-7.42 (m, 2H), 4.58 (tt, J=12.3, 4.0 Hz, 1H), 3.90 (t, J=6.4 Hz, 2H), 3.72 (d, J=13.0 Hz, 2H), 3.22-3.15 (m, 4H), 2.80 (qd, J=12.8, 3.0 Hz, 2H), 2.21 (d, J=13.7 Hz, 2H), 2.00-1.92 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]=[CH:12][N-:11][C:10]2=[S:14])=[CH:4][N:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][N:11]=[C:10]2[S:14][CH3:17])=[CH:4][N:3]=1
Reactant: CI
Reactant: S=C1[N-]C=CC1Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=NCCC1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.6 g of 3-(2-chloropyrid-5-yl-methyl)-pyrrolide-2-thione are added to a mixture of 0.1 g of sodium hydride (50% in oil) and 10 ml of dimethylformamide. The mixture is stirred for 20 minutes at room temperature and then 0.38 g of methyl iodide is added. The reaction mixture is stirred for a further 30 minutes at room temperature, poured onto ice-water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness by evaporation in vacuo. The title compound is obtained in the form of an oil (compound 3.2).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([N:9]([CH3:11])[CH3:10])=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]([O:25][CH2:26][CH3:27])=[CH2:24])CCC>C1(C)C=CC=CC=1.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.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH2:26]([O:25][C:23]([C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([N:9]([CH3:11])[CH3:10])=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14])=[CH2:24])[CH3:27]
Reactant: Cc1c(Br)c(F)c2oc(N(C)C)nc2c1C#N
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c(C#N)c2nc(N(C)C)oc2c1F
Yield: 65.8 %

Procedure:
6-Bromo-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-168) (0.80 g, 2.68 mmol) was dissolved in toluene (25 ml), then tributyl(1-ethoxyvinyl)tin (1.30 ml, 3.85 mmol), 2,6-di-tert-butylcresol (12 mg, 0.05 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.10 g, 0.14 mmol) were added followed by heating under reflux for 3 days. The insoluble matter was removed by filtration through Celite, followed by washing with ethyl acetate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:hexane=1:2 to 2:3 to 9:1 to dichloromethane:methanol=200:1) to obtain a brown solid (0.51 g, 66%).
Reaction SMILES: Cl.Cl.CN1CCNCC1.CN1CCNCC1.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](O)=[O:27]>C1COCC1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH:26]=[O:27]
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CN1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
LiA1H4 (7.6 g, 200 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (400 ml), then N-methylpiperazine dihydrochloride (17.3 g, 100 mmol) was added portionwise in 10 min. N-methylpiperazine (30 g, 300 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of benzothiophen-2-carboxylic acid (7.13 g, 40.0 mmol) in anhydrous THF (200 ml). The mixture was refluxed for 4 hours and after the same procedure as in preparation 6 pure title compound was obtained (4.6 g, 28.4 mmol, yield 70.9%) as dark orange crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:18]Br>CCOCC>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: BrBr
Reactant: CCCCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Anhydrous aluminum chloride (0.120 g.) is added to an ice-cooled solution of n-hexanophenone (21.1 g.) in anhydrous ether (20 ml.). The mixture is stirred and ice-cooled to a temperature below 10° C. during the dropwise addition of bromine (6.0 ml.) during 1 hour. The mixture is evaporated and the residual oil dissolved in ether (100 ml.). The solution obtained is washed first with a saturated aqueous solution of sodium thiosulphate (3× 30 ml.) and then with water. After drying (sodium sulphate) the ethereal solution is evaporated to give α-bromo-n-hexanophenone as an oil (28.0 g.) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:41]([N:44]=[C:45]=[O:46])[CH2:42][CH3:43].N12CCN(CC1)CC2>C1(C)C=CC=CC=1>[C:25]1([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:17][C@H:16]([C:37]([O:39][CH3:40])=[O:38])[CH2:15][O:14][C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:45]([NH:44][CH2:41][CH2:42][CH3:43])=[O:46])[CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](COc1cccc(-c2cccc(N)c2)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCN=C=O
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1cccc(-c2cccc(OC[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl O-(3′-amino-1,1′-biphenyl-3-yl)-N-triphenylmethyl-L-serinate (Example 2) (250.0 mg, 0.47 mmol, 1 equiv) was dissolved in toluene (5 mL) and treated at rt with n-propyl isocyanate (402.5 mg, 4.73 mmol, 10 equiv) and DABCO (1,4-diazabicyclo[2,2,2]octane) (5.3 mg, 0.05 mmol, 0.1 equiv). The reaction mixture was stirred at rt for 14 h and then partitioned between toluene and sat. aqueous NH4Cl solution. The organic layer was separated and dried over NaSO4 and the solvents were removed in vacuuo. The crude product was titurated with petroleum ether to give a yellow solid. Yield 210.0 mg, 72.4%. 1H NMR (CDCl3, 200 MHz) δ 7.65-7.50 (m, 9H); 7.40-7.15 (m, 12H); 6.95 (d, 2H); 5.19-4.98 (m, 1H); 4.25 (dd, 1H); 4.03 (dd, 1H); 3.38-3.02 (m, 4H); 2.88 (d, 1H); 1.65-1.45 (m, 2H); 0.90 (t, 3H). MS (EI) 614 (M+H), 243 (CPh3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCF)cc2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 66.1 %

Procedure:
120 mg (0.19 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.11 ml tetrahydrofurane. 126 mg (0.39 mmol) cesium carbonate and 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 70 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 48 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane, 2 ml tetrahydrofurane and 126 mg (0.39 mmol) cesium carbonate were added and the mixture stirred at room temperature for 24 hours. 64 mg (0.37 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 84 mg (62%) tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][C:15]=2[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:35]([C:37]#[N:38])[Na]>C(O)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][N:13]2[C:14]3[C:15](=[CH:16][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:18][CH:19]=3)[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=3)=[N:38][C:37]2=[O:35])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C#CCOc1ccc(NCCc2cc(OC)cc(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#CO[Na]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CCc1cc(OC)cc(OC)c1

Procedure:
A solution of 15 mg (33 μmol) {2-[2-(3,5-dimethoxy-phenyl)-ethylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone and 2.1 mg (33 μmol) NaOCN in 300 μl acetic acid is stirred for 1 h at rt. The solvent is evaporated and the product is recrystallised from CH2Cl2/diethyl ether.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[OH:33])=[C:14]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:15]2=[N:16][C:17]=1[CH3:18])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([O:5][CH:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[OH:33])=[C:14]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:15]2=[N:16][C:17]=1[CH3:18])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)c(O)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
To a stirred solution of the major diastereoisomeric pair of ethyl tert-butoxy[4-(2-hydroxy-4-methylphenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (Step 9, 214 mg, 458 μmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added a solution of sodium hydroxide (2 N, aqueous, 2 mL, 2.75 mmol) and the reaction was stirred at 60° C. for 18 hours. The reaction was concentrated in vacuo until all organic solvents had been removed, the aqueous residue was then acidified with hydrochloric acid (2 N, aqueous) to pH 2. The precipitated solid was collected by filtration and washed with tert-butyl methyl ether (10 mL) and dried in vacuo to give a mixture of diastereoisomers of the title compound as a white solid, 76 mg, in a 38% yield. LC-MS (12 min acidic) 5.51 mins 81% pure by UV, ES+/APCI+ 440, ES−/APCI− 438. 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (s, 9 H) 1.66-1.88 (m, 4 H) 2.09-2.21 (m, 2 H) 2.40 (s, 3 H) 2.73 (s, 3 H) 2.82 (t, 2 H) 5.33 (s, 1 H) 6.78 (s, 1 H) 6.85 (d, 1 H) 7.36 (d, 1 H).