Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:35]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(N)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (33 mg, 0.09 mmol) is solved in 3 ml dry-Dioxane. Benzylisocyanate (10.6 μl, 0.086 mmol) is added and the reaction is stirred at room temperature for 1 h. Evaporation of the solvent and flash-chromatography, Dichloromethane/Methanol (7:1) afforded the product: Cal. 515.6 found (M)+ 515.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:5][CH2:4][C:3]([O:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)[CH2:6][CH3:7])[C:27]#[CH:26]
Reactant: CCC(CO)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: C#CCBr
Product: C#CCOCC(CC)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 92 %

Procedure:
Using the procedure described in Example 8, 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]butan-1-ol (Example 6) was reacted with prop-2-ynyl bromide to give 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]but-1-yl prop-2-ynyl ether in 92% yield, m.p. 54° C.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[S:29]1[CH2:33][CH:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][CH2:30]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:31]2[CH:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][S:29][CH2:30]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CSCN1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
One-tenth mole of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carbethoxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: C(O)(=O)C.C[Si](N[Si](C)(C)C)(C)C.[I:14][C:15]1[S:19][C:18]([C:20](=O)[CH3:21])=[CH:17][C:16]=1[CH3:23].[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25]>CCOC(C)=O>[CH2:30]([O:29][C:27](=[O:28])[C:26]([C:24]#[N:25])=[C:20]([C:18]1[S:19][C:15]([I:14])=[C:16]([CH3:23])[CH:17]=1)[CH3:21])[CH3:31]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cc(C)c(I)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cc(C)c(I)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Acetic acid (9.4 ml) was placed in a flask at rt and HMDS (3.0 ml, 14.1 mmol) was added dropwise. After the exotherm subsided, 1-(5-Iodo-4-methyl-thiophen-2-yl)-ethanone (2.5 g, 9.4 mmol) was added as a solid followed by ethyl cyanoacetate (2.0 ml, 18.8 mmol). The reaction was stirred at 80° C. for 8 h, cooled to rt and concentrated by rotary evaporation to give a brown residue. The residue was taken up in EtOAc, washed with NaHCO3 (aq, sat.) and then with H2O. The organics were dried (NaSO4), filtered and concentrated to give a brown solid. The solid was triturated with EtOH and filtered to give 2-Cyano-3-(5-iodo-4-methyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (2.0 g, 5.5 mmol, 58%) as a light yellow solid. MS (ESI) m/z 362.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, 1H) 2.21 (s, 1H) 2.66 (s, 1H) 4.26 (q, 1H) 7.67 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])(=[O:30])=[O:29])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[N:15](COCC[Si](C)(C)C)[C:11]=2[CH:10]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:30])=[CH:25][C:12]2[N:13]=[C:14]([CH3:24])[NH:15][C:11]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2NS(=O)(=O)c2ccc(Cl)cc2Cl)nc(C)n3COCC[Si](C)(C)C)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2cc3[nH]c(C)nc3cc2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(6-(2,4-dichlorophenylsulfonamido)-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.245 g, 0.358 mmol) was dissolved in dichloromethane (4.0 mL). Trifluoroacetic acid (2.5 mL) was added and the reaction was allowed to stir overnight at room temperature. The reaction was diluted with ethyl acetate and saturated NaHCO3 (aq). The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 7% methanol in dichloromethane, afforded the title compound. LC-MS ESI (pos.) m/z: 555.8 (M+H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O>C(Cl)Cl>[CH3:23][CH:20]([CH2:21][CH3:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: CCC(C)Cc1ccc(-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(C)Cc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of 33 m moles(8.2 g) of boron tribromide in 25 ml of methylene chloride was cooled to -70° C., and a solution of 28 m moles(7.0 g) of 4'-methoxy-4-(2-methylbutyl)biphenyl in 150 ml of methylene chloride was added dropwise thereto. The mixture was returned to room temperature in 8 hours, and then stirred for five hours. After addition of water, the reaction mixture was extracted with methylene chloride, then purified by column chromatography to obtain 4.0 g of 4'-(2-methylbutyl)-4-hydroxybiphenyl. (yield: 60%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][C@@H:33]([C:35](O)=[O:36])[CH2:32][NH:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:33]3[CH2:32][NH:31][C:30](=[O:29])[NH:34]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1NC[C@H](C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@H]3CNC(=O)N3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.277 mmol) prepared in the previous step in chloroform (1 ml) were sequentially added (R)-2-oxoimidazolidine-4-carboxylic acid (40 mg) and WSC.HCl (64 mg) at room temperature, and the mixture was stirred for 3 hours. This reaction mixture was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (56 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:3]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2cccc(C)c2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2nc(C(C)Br)n(-c3ccc(F)cc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a mixture of 1.969 g 2-ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX) (6.974 mmol, 1.000 equiv) and 0.687 g sodium acetate (8.37 mmol, 1.20 equiv) in 28 mL glacial acetic acid at 40° C. (external temperature, oil bath) was added a solution of 0.372 mL bromine (7.32 mmol, 1.05 equiv) dissolved in 5 mL glacial acetic acid dropwise by addition funnel over 30 min. After 2 h the reaction solution was poured into 250 mL water. The resulting mixture was stirred vigorously at room temperature for 1 h, after which time the precipitate was collected by vacuum filtration, rinsing with warm (ca. 40° C.) water (3×50 mL). The solid was dried in vacuo over phosphorous pentoxide overnight, affording 2.19 g of a white solid. m.p. decomposes upon heating. 1H NMR (CDCl3) δ2.04 (d, 3H, J=6.8 Hz), 2.82 (s, 3H), 4.51 (q, 1H, J=6.8 Hz), 7.15 (ddd, 1H, J1=2.4 Hz, J2=4.4 Hz, J3=8.4 Hz), 7.23 (dd, 1H, J1=2.8 Hz, J2=10.8 Hz), 7.25-7.31 (m, 2H), 7.56 (ddd, J1=2.8 Hz, J2=4.8 Hz, J3=8.8 Hz), 7.64 (2×d, 2×1H, J=5.2 Hz) ppm. MS (ESI+) 361.1 [MH]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15]OCC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][NH:24][N:23]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)acetoacetamide (1 g) in 3 mL of ethanol is stirred overnight with 0.3 g of hydrazine hydrate. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 0.3 g of 3-methyl-4-[4-(trifluoromethyl)phenylaminocarbonyl]pyrazole as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17](C(OCCCC)=O)[CH2:16][CH2:15]3)[CH:13]=[N:12][C:9]2=[CH:10][CH:11]=1)[CH3:2].[CH:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][CH2:15]3)[CH2:13][NH:12][C:9]2=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)OC=O
Reactant: CCCCOC(=O)N1CCC2(C=Nc3ccc(CC(=O)OCC)cc32)CC1
Product: CCOC(=O)Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2

Procedure:
tert-butyl 5-(2-ethoxy-2-oxoethyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 2, substituting tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate with butyl 5-(2-ethoxy-2-oxoethyl)spiro[indole-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 275.2 [M+H-Boc]+; Rt=3.58 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[C:14]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:13]=1[CH3:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[C:14]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)[C:13]=2[CH3:31])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(Br)c3)c2C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A screwcap vial was charged with a solution of 5-bromopyridin-3-amine (273 mg, 1.58 mmol) in dry DMF (8 mL) under nitrogen. To this stirring solution was slowly added sodium hydride (63.0 mg, 1.58 mmol), followed 5 min later by 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (400 mg, 1.31 mmol). The reaction mixture was then stirred at rt for 6 h. Additional portions of sodium hydride (1.2 equivalents) were added after 2 and 4 h of stirring. Upon completion, the reaction was quenched with 10% aq. sodium carbonate and the product was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, and cond. The resulting crude residue was purified by flash-chromatography (silica gel, 0-60% EtOAc in hexanes) and subsequently by recrystallization in MeOH. This afforded N-(5-bromopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=441.0 (M+1).
Reaction SMILES: C(Cl)CCl.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:47]([OH:49])=O)=[CH:16][C:17]=3[N:18]3[CH2:24][C:23]([C:25]4[N:29]([CH:30]5[CH2:32][CH2:31]5)[N:28]=[C:27]([CH:33]([CH3:35])[CH3:34])[C:26]=4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][C:21]4[CH:41]=[C:42]([O:45][CH3:46])[CH:43]=[CH:44][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:50][CH:51]([S:53]([NH2:56])(=[O:55])=[O:54])[CH3:52]>CN(C1C=CN=CC=1)C.ClC(Cl)C.CCOC(C)=O>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:47](=[O:49])[NH:56][S:53]([CH:51]([CH3:52])[CH3:50])(=[O:55])=[O:54])=[CH:16][C:17]=3[N:18]3[CH2:24][C:23]([C:25]4[N:29]([CH:30]5[CH2:31][CH2:32]5)[N:28]=[C:27]([CH:33]([CH3:35])[CH3:34])[C:26]=4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][C:21]4[CH:41]=[C:42]([O:45][CH3:46])[CH:43]=[CH:44][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)S(N)(=O)=O
Reactant: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1c(C(C)C)nn(C2CC2)c1C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C(C)C)cc3n2C1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
EDC (151 mg, 0.790 mmol) was added to a stirring solution of 13-cyclohexyl-6-(1-cyclopropyl-4-(ethoxycarbonyl)-3-isopropyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (320 mg, 0.527 mmol), propane-2-sulfonamide (227 mg, 1.843 mmol), DMAP (193 mg, 1.58 mmol) in dichloroethane (5 mL) at room temperature. The reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, sat NaHCO3 and Brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product (375 mg, 0.526 mmol, quant) as a light brown residue consistent by LCMS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:29])[F:30])[CH:16]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (4.25 g, 17.24 mmol) in dichloromethane (30 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclohex-2-enone (4.00 g, 15.67 mmol) in dichloromethane (60 mL) and the resulting mixture is heated at reflux for 3 h and stirred at room temperature over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 100:0 to 98:2). Yield: 5.10 g; ESI mass spectrum: [(79Br)-M+H]+=465, [(81Br)-M+H]+=467; Retention time HPLC: 1.44 min (V001—006).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:20]\2=[O:21])=[CH:12][N:11]=[N:10]1)=[O:5])[CH3:2].ClCCl.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:19][CH:20]\2[OH:21])=[CH:12][N:11]=[N:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Yield: 100.7 %

Procedure:
To a solution of (E)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (14.48 g) in a mixed solvent of dichloromethane (50 ml) and ethanol (200 ml) was added sodium borohydride (1.13 g) with stirring under ice-cooling. After the resulting mixture was stirred at room temperature for 30 minutes, the reaction was stopped by addition of an aqueous ammonium chloride solution. The product was extracted with ethyl acetate. After the organic layer was washed with a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. Solvents were removed under reduced pressure to afford the title compound (14.63 g, yield: quantitative) as a colourless crystalline solid.
Reaction SMILES: NC1C=CC(OP2(OC3C=CC(N)=CC=3)N=P(OC3C=CC=CC=3)(OC3C=CC=CC=3)N=P(OC3C=CC(N)=CC=3)(OC3C=CC(N)=CC=3)N=2)=CC=1.[NH2:53][C:54]1[CH:105]=[CH:104][C:57]([O:58][P:59]2([O:96][C:97]3[CH:102]=[CH:101][C:100](N)=[CH:99][CH:98]=3)[N:64]=[P:63]([O:72][C:73]3[CH:78]=[CH:77][C:76]([NH2:79])=[CH:75][CH:74]=3)([O:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[N:62]=[P:61]([O:88][C:89]3[CH:94]=[CH:93][C:92]([NH2:95])=[CH:91][CH:90]=3)([O:80][C:81]3[CH:86]=[CH:85][C:84](N)=[CH:83][CH:82]=3)[N:60]=2)=[CH:56][CH:55]=1>>[NH2:53][C:54]1[CH:105]=[CH:104][C:57]([O:58][P:59]2([O:96][C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)[N:64]=[P:63]([O:72][C:73]3[CH:74]=[CH:75][C:76]([NH2:79])=[CH:77][CH:78]=3)([O:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[N:62]=[P:61]([O:88][C:89]3[CH:94]=[CH:93][C:92]([NH2:95])=[CH:91][CH:90]=3)([O:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[N:60]=2)=[CH:56][CH:55]=1
Reactant: Nc1ccc(OP2(Oc3ccccc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=N2)cc1
Agent: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccccc3)(Oc3ccccc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=N2)cc1
Product: Nc1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=NP(Oc3ccccc3)(Oc3ccc(N)cc3)=N2)cc1

Procedure:
Similarly proceeding as is described in Subpart (a) of this preparation using sufficient PtO2 and hydrogen and using the substituted triphosphazene of Preparation C, Subpart (b); Subpart (c) and Subpart (d), there is obtained the corresponding bis(4-aminophenoxy)tetrakisphenoxycyclotriphosphazene; tetrakis(4-aminophenoxy)bisphenoxycyclotriphosphazene; and pentakis(4-aminophenoxy)phenoxycyclotriphosphazene, respectively.
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10](Br)[C:11]#[CH:12].C(OC(C)C)(C)C>[Cl-].[Zn+2].[Cl-].C(Br)C#C.O1CCCC1>[OH:8][CH:7]([C:6]1[O:9][C:3]([CH3:2])=[CH:4][CH:5]=1)[CH2:12][C:11]#[CH:10]
Reactant: C#CCBr
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C#CCC(O)c1ccc(C)o1
Temperature: 10 °C
Yield: 80.6 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (14.6 g), dry zinc chloride (6.8 g) and dry tetrahydrofuran (110 g). Propargyl bromide (0.88 g) was added thereto at 10° C. while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the heat generation stopped, a mixture of 5-methylfurfural (55.06 g), propargyl bromide (64.5 g), tetrahydrofuran (55 g) and isopropyl ether (55 g) was dropwise added to the reaction mixture at 50° C. in 1.5 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to give 2-(1-hydroxy-3-butynyl)-5-methylfuran (60.5 g) in a yield of 81% (based on the starting 5-methylfurfural).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:11][CH2:12][C:13]([NH:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (30 g, 0.1857 mol) in CH2Cl2, (460 mL) TEA (77.6 mL, 0.557 mol) was added at 0° C. To the resulting mixture, chloroacetyl chloride (14.78 mL, 0.1857 mol) was added drop wise and the solution was stirred for 60 h at RT. The crude product was washed through a plug of silica gel with CH2Cl2 and purified through column chromatography using 100% CH2Cl2→25%→50%→75% 90:10:1 CH2Cl2:MeOH:NH4OH. The solution was concentrated in vacuo to give the title compound. MS (ESI, pos. ion) m/z: 202 (M+1). Mass calc'd for C8H8ClNO3: 201.02.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(CCl)cc1)c1cccs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sulfoxide is heated to 60° C and there are added at once 9.5 parts of α-chloro-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted five times with ether; the combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[p-(2-thenoyl)phenyl]acetonitrile as a residue.