Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61]CCCCCCCCCCCCCCCCCC)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:43]([NH:61][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.C[I:24].[C:25](#N)C>CCOCC>[I-:24].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][N+:10]2[CH:14]=[CH:13][N:12]([CH3:25])[CH:11]=2)=[CH:21][CH:22]=1
Reactant: CC#N
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccccc2)cc1
Reactant: CI
Solvent: CCOCC
Product: Cn1cc[n+](CC(OCc2ccc(Cl)cc2)c2ccccc2)c1
Product: [I-]

Procedure:
A mixture of 6.6 parts of 1-[β-(p-chlorobenzyloxy)phenethyl]imidazole, 4.2 parts of methyl iodide and 24 parts of acetonitrile is stirred and refluxed for 4 hours. Upon the addition of 80 parts of ether, the quaternary salt is precipitated. It is filtered off and crystallized from a mixture of 24 parts of acetone and 24 parts of diisopropyl ether, yielding 5 parts of 1-[β-(p-chlorobenzyloxy)phenethyl]-3-methylimidazolium iodide; mp. 112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][NH2:28]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:27]([CH3:26])[N:28]=[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: CNN
Solvent: CO
Product: Cn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
4-(3-Oxo-4-phenyl-butyryl)-piperidine-1-carboxylic acid tert-butyl ester (0.118 g) was dissolved in MeOH (4 mL) and added to a refluxing solution of methyl hydrazine (0.019 g) in methanol (2 mL). After 45 minutes at reflux the reaction mixture was cooled to room temperature and solvents evaporated under reduced pressure to give the crude product as a clear oil which was purified by column chromatography on silica using Et2O as eluent to give 4-(5-benzyl-2-methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.032 g) as a clear oil; NMR (CDCl3): 1.46 (s, 9H), 1.46-1.54 (m, 2H), 1.82 (br d, 2H), 2.64 (tt, 1H), 2.78 (br t, 2H), 3.77 (s, 3H), 3.90 (s, 2H), 4.18 (br d, 2H), 5.72 (s, 1H), 7.16-7.29 (m, 5H); MS: 356 (MH+).
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[N:10]=1)=[O:5].[C:13](=[O:16])([O-])[OH:14].[Na+].C(=O)([O-])ON1C(=O)CC([CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)C1=O>>[CH:29]1[C:28]2[CH:27]([CH2:26][O:14][C:13]([NH:11][C:9]3[N:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]([CH3:12])[CH:8]=3)=[O:16])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: O=C([O-])O
Reactant: O=C([O-])ON1C(=O)CC(CC2c3ccccc3-c3ccccc32)C1=O
Reactant: COC(=O)c1nc(N)cn1C
Agent: Cl
Agent: [Na+]
Product: Cn1cc(NC(=O)OCC2c3ccccc3-c3ccccc32)nc1C(=O)O
Reaction time: 8 h
Yield: 70.9 %

Procedure:
After dissolving 10 (8.24 g, 41.9 mmol) into distilled water (60 ml), sodium hydroxide (4.2 g) was added to the solution. After stirring overnight, the solution was neutralized with 1N hydrochloric acid, followed by distillation under a reduced pressure. The residue was dissolved into a mixed solution of water and ethyleneglycoldimethylether (200 ml, 1:1, v/v) to be used for the next reaction. After dissolving sodium hydrogen carbonate (14.1 g) into the solution, 9-fluorenylmethylsuccinimidyl carbonate (16.9 g, 50.1 mmol) was added thereto. After stirring the mixture overnight, precipitates were collected by filtration to obtain 12 (10.8 g, 29.7 mmol). After acidifying the filtrate with 10% hydrochloric acid, precipitates thus generated were collected by filtration and washed with ethyl acetate to further obtain 12 (1.2 g, 3.30 mmol). (Total yield: 12.0 g, 79%)
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+].CCOCC>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][CH2:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: OCCc1cc2ccccc2s1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCc1cc2ccccc2s1

Procedure:
2-Benzo[b]-thiopheneethanol (2.20 g), 1,6-dibromohexane (2.59 ml), TAB (0.25 g), aqueous 12.5M sodium hydroxide (9 ml), and ether (20 ml) were stirred overnight at room temperature. The mixture was diluted with water (50 ml), extracted with ether (3×50 ml), and the combined, dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0→98.2) to give the title compound as a colourless oil (2.73 g). Analysis Found: C, 56.55; H, 6.3; Br, 23.8; S, 9.4. C16H21BrOS requires C, 56.3; H, 6.2; Br, 23.4; S, 9.4%.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[S:9])[CH2:3][CH2:2]1.P(Cl)(Cl)(O[Cl:20])=O>C(#N)C>[ClH:20].[CH:1]1([NH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C(CNC(=S)c1cccnc1)NC1CC1
Reactant: O=P(Cl)(Cl)OCl
Solvent: CC#N
Product: Cl
Product: c1cncc(-c2ncc(NC3CC3)s2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
N-Cyclopropyl-2-(pyridine-3-carbothioamido)acetamide (1.00 g, 4.25 mmol) was dissolved in acetonitrile (5 mL) in a dry flask and phosphoryloxy trichloride (3.26 g, 21.25 mmol) was added, dropwise. The mixture was warmed to 100° C. and stirred for 1 hour. The mixture was cooled to room temperature and the yellow solid filtered under vacuum. This solid was washed with acetonitrile and dried under vacuum to give 0.36 g of N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine HCl salt (LCMS and 1H-NMR indicated 100% purity). The filtrate was diluted with ethyl acetate and carefully basified with saturated aqueous NaHCO3. The organic phase was separated and washed with brine, dried over MgSO4, and concentrated in vacuo to give N-cyclopropyl-2-(pyridin-3-yl)thiazol-5-amine as a brown oil (0.45 g, 3.47 mmol, 82%): 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J=2.1 Hz, 1H), 8.68 (dd, J=5.5, 1.2 Hz, 1H), 8.63-8.58 (m, 1H), 7.89 (dd, J=8.1, 5.4 Hz, 1H), 7.07 (d, J=7.8, 1H), 2.57 (dt, J=10.0, 3.3 Hz, 1H), 0.85-0.68 (m, 2H), 0.57-0.45 (m, 2H); ESIMS (m/z) 216 ([M−H]−).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[N+]([O-])=O)[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[S:2][CH3:1])[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CSc1ccc(C(=O)OC2CCCC2)cc1OC1CCCC1
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Sodium thiomethoxide (0.177 g, 2.5 mmol) is added portionwise to a stirred solution of cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (0.64 g, 2 mmol) in N,N'-dimethylimidazolidinone (10 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (100 mL) containing sodium chloride (15 g) and extracted with ethyl acetate (2×50 mL). The combined extract is washed with saturated brine (1×100 mL) and then dried over magnesium sulfate and evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.52 g, 81%) as a brown viscous oil which is used without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:26][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH:21][CH:22]=2)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 20 h

Procedure:
A solution of 18.8 g of trans-4-propylcyclohexanecarbonyl chloride in 20 ml of toluene was added dropwise to a solution of 18.8 of 4'-fluoro-4-hydroxybiphenyl and 8 g of pyridine in 25 ml of toluene and the mixture was heated, with stirring, at 80° for 20 hours. After cooling down water was added, the phases were separated, the organic phase was washed, evaporated and 4'-fluorobiphenyl-4-yl trans-4-propylcyclohexanecarboxylate was obtained, m.p. 96°, c.p. 174°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29]OS(C)(=O)=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29][O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])ccc2Cl)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To the mixture of 2-chloro-5-nitro-phenol (1.31 g, 7.54 mmol) and K2CO3 (1.57 g, 11.31 mmol) in 20 mL of DMF was added 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 7.54 mol). The reaction mixture was stirred at 50° C. for 1 h. After cooling to RT, the reaction mixture was diluted in 100 mL of EtOAc and quenched with 50 mL of water. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuum. The title compound was obtained via column chromatography (silica gel, 1;1 hexane/EtOAc) as yellow oil with 93% yield.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10](=[N:23][NH2:24])([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.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1(B(O)O)C=CC=CC=1>[C:10](=[N:23][NH:24][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(F)cnc1Br
Agent: CC(C)(C)[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(F)cnc1NN=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 2-bromo-5-fluoro-3-methyl-pyridine (190 mg, 1.0 mmol), benzhydrylidene-hydrazine (216 mg, 1.1 mmol), phenylboronic acid (5 mol %, 6 mg) and potassium tert-butoxide (157 mg, 1.4 mmol) in anhydrous toluene (6 mL) was degassed with a stream of argon, treated with Pd(OAc)2 (2 mol %, 5 mg) and racemic (1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) (2 mol %, 12 mg) and stirred at 80° C. for 1 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water followed by a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM followed by 100% DCM, to afford the title compound (196 mg, 64%). LCMS (Method 4): Rt 3.44 min, m/z 306 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc2[nH]ccc2c1
Product: CC(C)C(=O)NCc1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in intermediate-1, using (1H-indol-5-yl)methanamine and isobutyryl chloride (169 mg, 99%); MS: 217.0 (M+1).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH:29](Br)[CH2:30]Br)[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:30][CH:29]2[C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccccc1
Temperature: 40 °C
Yield: 29.2 %

Procedure:
A mixture of this ethylenediamine (31 g, 0.137 mole) and triethylamine (28 g, 0.277 mole) was added dropwise over 30 minutes to a stirred solution of ethyl-2,3-dibromopropionate (35.0 g, 0.135 mole) dissolved in 200 mL of toluene and heated to 40° C. After the addition was complete, the reaction was heated at 80°-85° C. for 7 hours, cooled to room temperature, and partitioned between water and toluene. The organic layer was separated, dried, and stripped of all solvent under reduced pressure to yield 38 g of the crude product. Chromatographic purification gave 12.8 g of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:26][CH2:25][C:22]2[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=2)=[O:17])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Reactant: Cc1ncc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 5-bromo-4′-methylbiphenyl-3-carboxylic acid (1.00 g, 2.75 mmol), (2-methylpyrimidin-5-yl)methanamine (0.406 g, 3.30 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumh (2.40 g, 6.32 mmol), N,N-diisopropylethylamine (1.91 mL, 11.0 mmol) and N,N-dimethylformamide (10 mL, 100 mmol) and the reaction stirred for 3 hours. The reaction was then quenched with water and extracted with ethyl acetate and washed with brine. The solvents were removed under reduced pressure and the residue purified by flash chromatography followed by prep HPLC to get the product as light yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10](C3C=CC(Cl)=CC=3)=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=2[N:6]=1.[CH3:21][NH:22][CH3:23].C1COCC1>CN(C=O)C>[CH3:19][O:18][C:9]1[C:8]([CH3:20])=[CH:7][C:5]2[N:6]=[C:2]([N:22]([CH3:23])[CH3:21])[S:3][C:4]=2[CH:10]=1
Reactant: CNC
Reactant: COc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2sc(N(C)C)nc2cc1C
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (135 mg, 0.37 mmol) in DMF (2 ml), was added dimethylamine in THF (2M, 0.46 ml, 0.92 mmol). The reaction mixture was stirred at 80° C. After the reaction finished, the reaction was cooled and concentrated. The residue was purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C17H17ClN2OS: 333.1 (M+H+). Found: 333.1 (M+H+).
Reaction SMILES: [OH2:1].[OH-].[Na+].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11](Cl)(Cl)=[O:12]>C(Cl)Cl>[C:11](=[O:12])([O:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: O
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Oc1ccccc1)Oc1ccccc1
Temperature: 33 °C
Yield: 99.9 %

Procedure:
A mixture comprising 103 kg/hour of deionised water, 42.2 kg/hour 50% NaOH and 48.3 kg/hour phenol was continuously combined with a solution comprising 86.2 kg/hour methylene chloride and 27.5 kg/hour phosgene (8 mol % excess with respect to phenol) in a vertical, cooled tubular reactor. The reaction mixture was cooled to a temperature of 33° C., and a pH of 11.5 was measured after an average residence time of 15 seconds. 5.4 kg/hour of 50% NaOH were then added to said reaction mixture in the second step of the process, so that after a further residence time of 5 minutes the pH in the second reaction step was 8.5. In this continuously operated reaction, any fluctuations in the rates of addition which occurred were compensated for by adjusting the rate of addition of NaOH in each case. In the second step of the process, the reaction mixture was continuously mixed by passing it through a tube provided with constrictions. After the renewed addition of NaOH, the reaction temperature was adjusted to 30° C. by cooling. The aqueous, slightly alkaline phase contained 20 ppm phenol. The DPC yield was correspondingly high, namely 99.998% with respect to phenol. After separating the organic phase from the aqueous phase, the product was washed with 0.6% HCl and water, and 99.9% (as determined by GC) diphenyl carbonate was obtained after a final phase separation after removing the methylene chloride by evaporation.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[C:14]([O:18][C:19]([NH:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36](C=O)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[CH3:41]CCCCC>C1COCC1>[CH3:41][O:8][C:6](=[O:7])[CH:4]=[CH:5][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:29]2[CH:30]=[CH:31][C:26]([CH:22]([NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)=[CH:38][CH:37]=1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 4.03 g, 100.0 mmol) was washed with anhydrous hexane (3×50 mL) under an atmosphere of argon. Dry THF (200 mL) was added and cooled to 0-5° C. A solution of trimethylphosphonoacetate (8.2 mL, 50.0 mmol) in dry THF (35 mL) was added dropwise to the above mixture with stirring. After about 5 min, a solution of the aldehyde 29 (17.0 g, 46.0 mmol) in dry THF (35 mL) was added and the reaction mixture was then brought up to room temperature and stirred. After 30 min, the clear reaction mixture was quenched with 10% citric acid (50 mL) and further acidified to pH ˜2.0 with 2.0 M HCl. THF was evaporated under reduced pressure and the resulting oily material was extracted with EtOAc (2×400 mL). The organic layer was extracted with water (3×500 mL), and brine (1×500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the unsaturated ester 30 (20.0 g, quantitative yield) as a crude product that was taken for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): 12.9 (br, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.65 (d, J=12.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.56 (d, J=12.0 Hz, 1H), 5.12 (d, J=8.0 Hz, 1H), 3.72 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH:15]([OH:17])[CH3:16]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:15]([CH3:16])[CH2:14][CH:13]([CH3:12])[CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)CC(C)CC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CC(C)CC(C)C)cc1

Procedure:
9.4 g. of p-toluenesulfonyl chloride are added with ice cooling to a solution of 6.5 g. of 4,6-dimethyl-2-heptanol in 50 ml. of anhydrous pyridine and the mixture is left for 24 hours at 5° C. Thereafter, the mixture is poured onto ice-water and extracted three times with diethyl ether. The extracts are washed successively with cold 2-N aqueous hydrochloric acid solution, water and twice with saturated sodium chloride solution, dried over sodium sulfate/potassium carbonate and evaporated at room temperature, finally at 0.05 mmHg. There is obtained 1,3,5-trimethylhexyl p-toluenesulfonate which exhibits a spot in the thin-layer chromatogram [Rf = 0.43; hexane/ethyl acetate (9:1 parts by volume)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Br[C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:19][CH:18]=1.C(O[Na])(C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][C:20]1[CH:28]=[CH:29][C:17]([N:13]2[CH2:14][CH2:15][CH:10]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: CN(c1ccc(Cl)cc1)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(OC3CCCCO3)cc2)CC1
Yield: 29.6 %

Procedure:
4-(N-(4-chlorophenyl)-N-methylamino)-piperidine (2.52 g, 11.22 mmol), 2-(4-bromophenoxy) tetrahydropyran (2.89 g, 11.22 mmol), palladium acetate (50 mg, 0.22 mmol), (S)-(−)-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (212 mg, 0.34 mmol) and tert-butoxy sodium (1.51 g, 15.71 mmol) were refluxed with heating in toluene (30 ml) under nitrogen atmosphere for 3 hours. Ethyl acetate and water were added into the reaction solution and stirred, then the resulting precipitate was removed by filtration through Celite, thereafter the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and then filtered. After the resulting filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-(4-(tetrahydropyran-2-yloxy)phenyl)-4-(N-(4-chlorophenyl)-N-methylamino)piperidine (1.33 g, yield 30%) as a light yellow powder.