Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:37]([CH3:40])=[N:38][N:39]=3)[N:18]=[C:19]([C:21]3[N:22]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:30]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:21]1[C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]2[N:17]([C:37]([CH3:40])=[N:38][N:39]=2)[N:18]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2c(NC3CCNCC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reaction time: 1 h

Procedure:
4-[6-(1-Benzyl-1H-indol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (13 mg; 0.02 mmol) was dissolved in 1 ml DCM and treated with 300 μl TFA. It was stirred for 1 hour. The solvent was evaporated and the residue taken up in DCM and extracted with aqueous NaHCO3. The organic layer was dried and evaporated to dryness.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](#[N:16])[CH:14]=[CH2:15]>C1C=CC=CC=1.CO>[C:13]([CH2:14][CH2:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:16]
Reactant: C=CC#N
Reactant: CCOC(=O)Cc1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)C(CCC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-phenylacetate (5.00 g, 30.5 mmol) in benzene (50 mL) was added Triton-B (40% solution in methanol) (0.240 mL, 0.609 mmol) at 0° C. After stirring for 10 minutes, acrylonitrile (2.005 mL, 30.5 mmol) was added, and the reaction was allowed to warm to room temperature. The reaction was stirred for 3 hours, concentrated, loaded directly onto silica gel (GraceResolv High Resolution Flash Cartridge, 80 g) and eluted using a gradient of 5% to 40% ethyl acetate/hexanes over 40 minutes (flow rate=40 mL/minute). Concentration of product containing fractions provided the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.19 (m, 5H), 4.26-4.00 (m, 2H), 3.81-3.59 (m, 1H), 2.50-2.01 (m, 4H), 1.20 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].C[O:13][P:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([P:14](=[O:13])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: CCCCC(C)(CC)C(=O)Cl
Reactant: COP(c1ccccc1)c1ccccc1
Product: CCCCC(C)(CC)C(=O)P(=O)(c1ccccc1)c1ccccc1

Procedure:
Using a method similar to that of Example 1, 88 parts of 2-methyl-2-ethylhexanoic acid chloride and 108 parts of methoxydiphenylphosphine give 165 parts of 2-methyl-2-ethylhexanoyl-diphenylphosphine oxide as an oily crude product. Column chromatography over silica gel (eluant: a 3:1 mixture of toluene and ether) gives the product as a pale yellowish oil. Yield 154 parts (90% of theory).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH2:25][OH:26])[C:14]3[C:19]([C:20]=2[CH:21]=1)=[CH:18][C:17]([N:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=3)C1C=CC=CC=1.[C:27](O)(=O)C>CO.[Pd]>[CH3:23][N:22]([CH3:24])[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:25][O:26][CH3:27])[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:21][C:20]2=1
Reactant: CC(=O)O
Reactant: CN(C)c1ccc2c(c1)c1cc(OCc3ccccc3)ccc1n2CO
Agent: [Pd]
Solvent: CO
Product: COCn1c2ccc(O)cc2c2cc(N(C)C)ccc21
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of [3-(benzyloxy)-6-(dimethylamino)-9H-carbazol-9-yl]methanol 7 (120 mg,), Pd/C (100 mg) and acetic acid (cat. amount) in MeOH (15 mL) was hydrogenated at room temperature for 4 hrs. It was filtered through a short Celite pad. The filtrate was concentrated in vacuo to give the desired product (94 mg, 100%). 1H NMR (acetone-d6, 400 MHz) δ: 7.38-7.50 (m, 4H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 5.62 (s, 2H), 3.20 (s, 3H), 2.94 (s, 6H). MS: m/z=271 (M+H+)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[NH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:9]([O:8][CH2:7][CH:6]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(=O)OCC(=O)COC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OCC(COC(C)=O)NCC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (3.0 g, 17.24 mmol) on dichloroethane (70 ml) was added tert-butyl 2-aminoacetate (2.35 ml, 17.24 mmol). The reaction was stirred for 90 minutes before sodium triacetoxyborohydride (5.5 g, 25.86 mmol) was added and stirring was continued for 18 hours. The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-40% EtOAc:Hept to yield the title compound (1.93 g, 38% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 3.96-4.26 (4H, m), 3.30-3.45 (2H, m), 3.06 (1H, quin, 5.4 Hz), 2.09 (6H, s), 1.47 (9H, s).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (23.8 mg, 64.4%), MS (ISP) m/z=454.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][Cl:25])[CH:17]=[CH:16][N:15]=1>>[ClH:12].[ClH:11].[Cl:25][CH2:24][CH2:23][CH2:22][S:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=1[CH3:20]
Reactant: Cc1c(SCCCCl)ccnc1CCl
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Product: Cc1c(SCCCCl)ccnc1CSc1nc2ncccc2[nH]1
Yield: 88 %

Procedure:
According to the procedure described in Example C1., the reaction of 2-mercapto-1H-imidazo[4,5-b]pyridine with 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride gives the title compound as a colorless powder; m.p. 186-188° C.; yield: 88% of theory.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:18]2[S:19][CH2:15][CH2:16][N:17]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(N)cc1
Reactant: S=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCc1ccc(NC2=NCCS2)cc1
Temperature: 50 °C

Procedure:
A 2 liter, 3-neck round bottom flask fitted with magnetic stirrer, addition funnel, argon gas inlet and thermometer was charged with 4-hexylaniline (65.0 g, 0.367 m) dissolved in 500 ml reagent toluene. To this stirred solution, was added dropwise a solution of β-chloroethylisothiocyanate (53.5 g, 0.441 m, 1.2 eq.) in 175 ml toluene at room temperature. No significant exotherm was noted. After the addition was completed, the reaction mixture was warmed to 50° C. for 19 hours. The reaction was cooled to room temperature and the toluene removed on the rotary evaporator to give an orange, semi-solid residue which was stirred with 900 ml diethyl ether (Et2O). The resulting slurry of off-white solid was cooled in an ice water bath and the solid filtered, washed with cold Et2O, and dried (filter suction, desiccator) to give the slightly impure hydrochloride salt of the desired aminothiazoline. The HCl salt was neutralized by adding the salt to a cold, stirred solution of sodium hydroxide (14.7 g, 0.367 m) in 1200 ml water layered with Et2O. After neutralization, the ether layer was separated and the aqueous layer was extracted with Et2O four times. The combined Et2O extracts were washed with water twice and with a saturated NaCl solution once, dried (MgSO4), and evaporated under vacuum to afford 90.0 g of crude, freebase product as a waxy, off-white solid. The crude material was recrystallized from 900 ml hexane to give 73.0 g (76%) product in two crops as small, off-white platelets. m.p. 77°-79° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:30][CH2:31]O>C(Cl)Cl>[F:27][C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:30][CH2:31][I:25]
Reactant: OCC=CC(F)(F)C(F)(F)F
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)CCCI
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
446 mg of triphenylphosphine is dissolved in 2 cm3 of methylene chloride, cooled down to 10° C., 116 mg of imidazole is added, agitation is carried out for 15 minutes, 431 mg of iodine is added, agitation is carried out for 30 minutes, 0.21 cm3 of 4,4,5,5,5-pentafluoro 2-penten 1-ol is added, agitation is carried out for 4 hours at ambient temperature, the organic phase is washed with a saturated aqueous solution of sodium thiosulphate and a chloromethylenic solution of 4,4,5,5,5-pentafluoro iodopentane is obtained which is used as it is in the continuation of the synthesis. The operation is carried out as indicated in Example 8 Stage F, starting with 618 mg of the thioacetate prepared below in 7 cm3 of methanol and the chloromethylenic solution of the iodated derivative prepared above. 1.2 g of expected product is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)n1

Procedure:
Compound 628 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H26N6O4: 511.20; found: 511.04.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([C@H:36]([OH:38])[CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:38][C@H:36]([CH3:37])[C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:23])[CH2:34][OH:35]
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (2R,3R)-2-aminobutane-1,3-diol (25 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by trituration with 1:1 heptane/dichloromethane to afford 115 mg (96%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a white solid. MS: [M+H]+=529.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ClN1C(=[O:19])CCC1=O>CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[O:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cccc(S(N)(=O)=O)c1
Solvent: CO
Product: CS(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-methylsulfanyl-benzenesulfonamide (406 mg, 2 mmol) and N-chlorosuccinimide (268 mg, 2 mmol) in methanol was stirred at room temperature for 8 hours. The methanol was evaporated and the residue was slurried with methylene chloride and filtered. The filtrate was evaporated to give 250 mg of the titled compound as a white solid.
Reaction SMILES: [CH2:1](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1SCCCC)C1C=CC=CC=1.[CH2:26]([C:33]1[C:41]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[S:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[C:41]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][C:36]([C:37]([O:39][CH3:1])=[O:38])=[CH:35][C:34]=1[S:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cc1ccccc1
Product: COC(=O)c1cc(SCc2ccccc2)c(Cc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 124, 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid with 4-benzyl-3-benzylthio-5-sulfamylbenzoic acid and following the procedure described, methyl 4-benzyl-3-benzylthio-5-sulfamylbenzoate is obtained with a melting point of 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 85.4 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-fluoro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (93.7 mg, 0.220 mmol) was dissolved in acetonitrile (6.6 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (115 mg, 0.880 mmol), acetic acid (0.252 mL, 4.40 mmol) and sodium triacetoxyborohydride (163 mg, 0.77 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-5-fluoro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (102 mg, yield 85%).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8](O)[C:9](C)([CH3:11])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:9]([CH3:11])([CH3:10])[CH2:1][O:2]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: CC(C)(C)CO
Reactant: COC=CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/OCC(C)(C)C
Temperature: 27.5 °C
Reaction time: 14 h

Procedure:
House vacuum was applied to a mixture of 4-methoxy-3-buten-2-one (14.0 g, 140 mmol) (Fisher Scientific), neopentyl alcohol (18.0 g. 200 mmol), pyrimidium p-toluenesulfonate (0.45 g, 1 mmol) and toluene (50 mL). This was stirred at 25-30° C. for 14 h. All solvent and volatiles were removed by vacuum and the residue was dissolved in hexane (75 mL). This was purified by chromatography (30% ethyl acetate/hexane) to give (E)-4-(2,2-dimethylpropoxy)but-3-en-2-one.
Reaction SMILES: C([O:5][C:6](=[O:52])[CH:7]([NH:12][C:13](=[O:51])[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=1[S:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=1[C:36](=[O:50])[NH:37][CH:38]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=2[C:36](=[O:50])[NH:37][CH:38]([C:43]([OH:45])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[C:14]([CH:19]=1)[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:52])=[O:5])=[O:51])(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)O)c(C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 77.3 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)] 2-{5-acetylamino-2-[4-acetylamino-2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-4-methyl-pentanoic acid tert-butyl ester (0.2 g, 0.2 mmol) from Example 44, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was recrystallized from dimethylformamide/water to afford 0.1 g of the title compound, mp 241-242° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:30][CH:31]=[C:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[N:42][C:37]=3[CH2:36][O:35][C:34]3[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]2=3)[CH2:13][CH2:12]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzoic acid methyl ester (0.23 g, 0.916 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% Methanol) to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10]([S:11][CH2:12][CH3:13])=[C:9]([C:14]([NH2:16])=[O:15])[CH:8]=[N:7][N:6]2[CH:17]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>CN1C(=O)CCC1>[CH2:12]([S:11][C:10]1[C:5]2[N:6]([CH:17]=[C:3]([C:1]3[NH:20][N:19]=[N:18][N:2]=3)[CH:4]=2)[N:7]=[CH:8][C:9]=1[C:14]([NH2:16])=[O:15])[CH3:13]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCSc1c(C(N)=O)cnn2cc(C#N)cc12
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12

Procedure:
A solution of 6-cyano-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (140 mg, 0.568 mmol) and azidotributyltin (0.187 mL, 0.682 mmol) in NMP (2.0 mL) was heated to 180° C. for 60 minutes under microwave oven (CEM). The reaction mixture was taken to the next step without purification. MS (ES+) m/z: 290.08 (M+H).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]([O:9]CC)=[O:8].C(O)C.Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F

Procedure:
A solution of 3.8 g of potassium hydroxide in 15 ml of water is added to a mixture of 3.5 g of ethyl 3-fluoro-4-hexadecylaminobenzoate, 30 ml of water and 30 ml of ethanol. Upon heating, a clear solution is formed and after 20 hours, the hot solution is acidified with concentrated hydrochloric acid and cooled. The precipitate is collected and recrystallized from ethanol and then from chloroform to yield 3-fluoro-4-(hexadecylamino)benzoic acid as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([CH3:21])[N:3]=1.Cl>C(O)C>[NH2:18][C:5]1[C:4]([CH3:21])=[N:3][C:2]([Cl:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Cl)nc(C)c([N+](=O)[O-])c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Cl)nc(C)c(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 15 ml of ethanol was dissolved 1.2 g of 2-chloro-3,4-diethoxycarbonyl-6-methyl-5-nitropyridine, whereto 1.9 g (9 eq.) of reduced iron was added, followed by adding dropwise 7.1 ml of hydrochloric acid. The mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, the residue was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off to give an oily product.