Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH2:21](OB(C=C)OCCCC)[CH2:22]CC.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([CH:21]=[CH2:22])[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Reactant: C=CB(OCCCC)OCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Yield: 84.8 %

Procedure:
5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, (300 mg, 0.85 mmol), vinylboronic acid dibutylester, (184 mg, 1.0 mmol), potassium carbonate, (420 mg, 3.0 mmol) and Pd(Ph3P)4 were combined in 3 mL DME and 1 mL water in a tube under nitrogen and heated in a microwave reactor to 130° C. for 10 min. The organic layer was then separated and evaporated. The residue was purified by silica chromatography (eluent: methylene chloride), affording 215 mg(85%) 1-(Toluene-4-sulfonyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine. MS ES+ 299.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[N:16][C:15]([NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ncc(Br)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc(NC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of 3-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (850 mg) in dry DCM (10 mL) was added slowly TFA (0.911 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (0.911 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[CH3:22])=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[CH2:22][Br:23])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1CBr
Yield: 59.7 %

Procedure:
A mixture of 5-bromo-1-(4-methoxy-benzyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.5 g, 9.6 mmol), N-bromosuccinimide (1.87 g, 10.5 mmol), and benzoyl peroxide (231 mg, 0.96 mmol) in CCl4 (90 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 2.55 g of the title compound. MS: (+) m/z 468.00 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20]#[C:21][CH3:22].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:21]([CH3:22])=[C:20]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC#CCBr
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.61 g; 2.2 mmol), 1-bromo-2-butyne (1.7 mL; 18.8 mmol) and indium (2.49 g; 21.7 mmol) were suspended in THF (10 mL) and 0.045 M HCl (20 mL) and stirred vigorously overnight. The reaction mixture was diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4. The resulting crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: CS([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=O)=O.[C:21]([O-])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].O>CN(C=O)C>[C:21]([CH:5]([OH:20])[C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cn([C@H]2C=C[C@@H](C(O)S(C)(=O)=O)O2)c(=O)[nH]c1=O
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5'-mesyl-d4T (6, 0.4 g) in 6 ml of DMF was added powdered sodium benzoate (0.24 g). The reaction was stirred at 100° C. for 6 hours. After cooling, water (30 ml) was added. The resulting precipitate was filtered, washed with 2×5 ml water and dried to give 5'-benzoly-d4T (7'), 0.04 g (91%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[CH:3]=1.C(N(CC)CC)C.CC1(C)C(C)(C)OBO1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:41]1[CH:50]=[CH:49][N:48]=[C:47]2[C:42]=1[CH:43]=[CH:44][C:45]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[N:46]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O.O1CCOCC1>[C:51]1([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[N:48][CH:49]=[CH:50][C:41]=3[C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:4][CH:3]=3)[N:46]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Clc1ccnc2nc(-c3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cccnc21
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: c1ccc(-c2ccc3c(-c4c[nH]c5ncccc45)ccnc3n2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A Schlenk tube is filled successively under nitrogen with 189 mg (0.55 mmol) of tert-butyl 3-iodopyrrolo[2,3-b]pyridine-1-carboxylate, 9.5 mg (8.2 μmol) of tetrakis(triphenylphosphine)palladium, 2.3 ml of dioxane, 0.23 ml (1.6 mmol) of triethylamine and 80 μml (0.55 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The reaction mixture is stirred at 80° C. for 3 hours under nitrogen. The reaction mixture is cooled to room temperature; 1 ml of water, 175 mg (2.1 mmol) of sodium carbonate, 22 mg (19 μmol) of tetrakis(triphenylphosphine)-palladium, 132 mg (0.55 mmol) of 5-chloro-2-phenyl-1,8-naphthyridine and 4.6 ml of 1,2-dimethoxyethane are added under a nitrogen atmosphere. The reaction mixture is stirred at 100° C. for 20 hours. The reaction mixture is cooled to room temperature and evaporated in vacuo. The residue is chromatographed on a silica-gel column with methanol/dichloromethane as eluent: 2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,8-naphthyridine (“A5”) as yellowish crystals; MS (ESI): 322 [M+H]+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][C:17]#[N:18])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(Cl)(Cl)Cl.[Pt]=O>[NH2:18][CH2:17][CH2:16][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)N(CCC#N)C(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)[C@@H](C)N(CCCN)C(=O)OC(C)(C)C

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-D-alaninate (1.5 g) in ethanol (80 mL) and chloroform (1.4 mL) was added platinum oxide (350 mg), and the reaction mixture was stirred over an atmosphere of hydrogen for 16 hr. The mixture was filtered through Celite, and the Celite washed with methanol and dichloromethane. The filtrate was concentrated to give methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:20]([CH2:27][CH2:28][CH3:29])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC(=CC(=O)OCC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl 3-oxo-caproate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-propylvinyl]ureido}-benzoate,
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([CH:36]=[C:37]([CH3:39])[CH:38]=2)[NH2:35])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]>CO.C(Cl)Cl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([NH:35][C:5]3[N:10]=[C:9]([N:11]4[CH:15]=[CH:14][N:13]=[C:12]4[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:8]=[CH:7][N:6]=3)[CH:36]=[C:37]([CH3:39])[CH:38]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCN(Cc2cc(C)cc(N)c2)CC1
Reactant: CS(=O)(=O)c1nccc(-n2ccnc2-c2ccccc2)n1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(Cc2cc(C)cc(Nc3nccc(-n4ccnc4-c4ccccc4)n3)c2)CC1
Temperature: 130 °C

Procedure:
2-(Methylsulfonyl)-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (1-3, 100 mg, 0.33 mmol) and 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylaniline (240 mg) were combined neat and heated to 130° C. After 2 hours the mixture was cooled to room temperature. Flash column chromatography (gradient, 2-5% MeOH/CH2Cl2) gave the title compound as an off-white foam. 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J=5.5 Hz, 1H), 7.68 (d, J=1.53 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 4H), 7.30 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 6.25 (d, J=5.49 Hz, 1H), 3.64 (t, J=5.19 Hz, 2H), 4H), 3.46 (m, 4H), 2.44 (m, 4H), 2.35 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CS(O[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1)(=O)=O>C1COCC1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Reactant: Nc1ncco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ncco2)CN1c1ccc(C2=CCOCC2)c(F)c1
Yield: 3.5 %

Procedure:
To a stirred partial solution of 2-aminooxazole(169 mg, 2.0 mmol) in dry THF (10 ml), cooled to −78° C., under argon, was added slowly n-BuLi(1.33M, 1.5 ml, 2.0 mmol), followed after 1 h by 5(R)-methylsulfonyloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (see Example 41; 371 mg, 1.0 mol) suspended in dry THF(20 ml). The reaction was allowed to come to room temperature and then refluxed for 24 h. The reaction was quenched with ammonium chloride solution(10%w/v, 30 ml), extracting the mixture with chloroform (3×50 ml). The extracts were dried (magnesium sulfate), concentrated by rotary evaporation chromatographed by MPLC (Merck 9385 silica, 3-10% gradient methanol/dichloromethane eluent) and the pure fractions combined, concentrated and triturated with diethyl ether to. give the title compound (25 mg, 4.6%). NMR (300 Mz, DMSO-d6), δ/ppm: 2.31 (m, 2H), 3.35 (m, 2H, obscured), 3.64 (dd, 1H), 3.84 (t, 2H), 3.90 (m, 1H), 4.15 (m, 1H), 4.24 (m, 2H), 4.46 (m, 1H), 5.97 (m, 1H), 6.90 (m, 1H), 7.19 (m, 2H, partially obscured), 7.37 (dd, 1H), 7.44 (dd, 1H). MS: ES+ (M+H)=360.
Reaction SMILES: [CH2:1]([C:8]1([N:26]([CH3:28])[CH3:27])[CH2:13][CH2:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=3)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br.CCO.C(OCC)(=O)C>[CH2:1]([C:8]1([N:26]([CH3:28])[CH3:27])[CH2:9][CH2:10][CH:11]([C:14]2[NH:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(C3=CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Agent: Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(C3CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(±)-N-[1-Benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)cyclohex-3-enyl]-N,N-dimethylamine (1.97 g, 5.26 mmol) was suspended in HBr/glacial acetic acid (33% HBr, 30 ml). Sn powder (3.12 g, 26.3 mmol) was then added to the mixture in portions in the course of 30 min. When the addition had ended, the reaction mixture was stirred at RT for a further 48 h.—For working up, the mixture was diluted with EtOH (20 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (100 ml). The aqueous mixture obtained was extracted with methylene chloride (4×20 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and then concentrated. The residue obtained (1.7 g) was dissolved in ethyl acetate (10 ml). The mixture was placed in a refrigerator for 2 h for crystallization. 1-Benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (less polar diastereoisomer) was separated off by filtration in a yield of 500 mg (25%) as a beige solid. The mother liquor was concentrated and the residue was purified by column chromatography [silica gel 60 G (150 g); EtOAc (1,000 ml)]. The polar product was obtained in a yield of 134 mg (7%) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:17][CH:16]=1)([O-])=O.[Sn](Cl)Cl.O>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[S:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:24][N:23]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-(6-nitroquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine (228 mg, 455 μmol) in 1 mL of DMF, was added tin (II) chloride (431 mg, 2273 μmol) and 115 uL of water. After 15 minutes of sonication, the reaction was stirred at rt. After 2 days, water was removed under vacuum azeotropically with benzene. DCM was added to the suspension. Yellow solids precipitated out of the solution and were filtered off with DCM. The filtrate was concentrated and purified by RPLC on an acidic Gilson column system. Fractions containing the product were washed with sat. NaHCO3. The product was extracted with DCM. The organic was washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified further by performing a column chromatography using 60:40 DCM:(90:10:1 DCM:MeOH:NH4OH). Yellow solid, N-(4-(6-aminoquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
A solution of 20.02 g (0.1 mol) of 3-acetylbenzenesulfonyl fluoride and 29 ml of morpholine in 100 mL of THF is stirred at room temperature for 16 hours. The solvent is removed, the residue dissolved in CH2C2, and solution washed with H20 and 2N HCl. The organic layer is dried (MgSO4), the solvent removed, and the residue crystallized from CH2Cl2 -hexane to give 25.2 g (93%) of light yellow crystals, m.p. 144°-147° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5](O)[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2].C(N(S(F)(F)[F:20])CC)C>C1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5]([F:20])[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2]
Reactant: CCOC(OCC)C(O)CN=[N+]=[N-]
Reactant: CCN(CC)S(F)(F)F
Solvent: c1ccccc1
Product: CCOC(OCC)C(F)CN=[N+]=[N-]
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of 3-azido-2-hydroxypropanal diethyl acetal (7.32 g, 38.73 mmol) in dry benzene (50 mL) was added diethylaminosulfurtrifluoride (DAST; 20.6 mL) at -78° C. After the addition, the solution was stirred at room temperature for an hour, then heated to 70° C. for 12 hours. The reaction was quenched by the addition of methanol at zero degrees C. and dilution with water. After dichloromethane extraction, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified with silica gel column chromatography (hexane: ether=9:1, volume/volume) to yield 3-azido-2-fluoropropanal diethyl acetal as an oil (65 percent); Rf =0.84 EtOAc:hexane=2:3) 1H-NMR (CD3Cl) δ 1.215~1.219 (6H, m) 3.526 (2H, dm, J=15.3 Hz), 3.642~3.670 (2H, m), 3.680~3.808 (2H, m), 4.514 (1H, dm, J=45.9 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH:39](=O)[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:37])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][N:34]([CH2:39][CH3:40])[CH2:33][CH2:32]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:38])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CCNCC3)cc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Yield: 55 %

Procedure:
The piperdine was reacted with acetaldehyde, Na(OAc)3BH in dichloromethane at room temperature overnight. Then washed with 1N NaOH, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (55%).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].[C:6](OCC)(OCC)([O:9][CH2:10][CH3:11])[CH2:7][CH3:8]>C(O)C>[CH2:10]([O:9][C:6](=[C:1]([C:4]#[N:5])[C:2]#[N:3])[CH2:7][CH3:8])[CH3:11]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#CCC#N
Solvent: CCO
Product: CCOC(CC)=C(C#N)C#N

Procedure:
33.03 g (0.5 mol) of malonodinitrile and 88.13 g (99.02 ml, 0.5 mol) of triethyl orthopropionate are heated at 100° C. for two hours, and the ethanol which is formed during this is distilled off overhead. The reaction mixture is left to cool and added to ca. 500 ml of water. The aqueous phase is extracted with ethyl acetate, then the organic phase is dried with sodium sulfate and, after filtering off the drying agent, is concentrated by evaporation. The resulting 72 g (purity ca. 90%) of (1-ethoxy-propylidene)malononitrile are used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1>ClS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:10](=[O:12])[CH2:9][CH2:8]2
Reactant: O=C(O)CCc1cccc(F)c1
Agent: O=S(=O)(O)Cl
Product: O=C1CCc2cc(F)ccc21
Yield: 67.7 %

Procedure:
3-(3-Fluorophenyl)propanoic acid (I-78b: 2.0 gm, 11.8 mmol) was cyclized with chlorosulfonic acid (20 mL) to afford the crude product. Purification by column chromatography on silica gel (10% ethyl acetate in hexane), afforded 1.2 g of the product (70.5% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[O:25][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CO>[CH3:26][O:25][C@H:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (4.28 g, 11.7 mmol) was dissolved in methanol (20 mL). A 4 N hydrochloric acid/ethyl acetate solution (60 mL) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with THF. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N1CC[O:46]CC1.N1CCCC1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][O:46][CH2:38][CH2:39]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN5CCCC5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN5CCOCC5)c4)cc23)CC1
Yield: 34 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (70 μL, 0.71 mmol) for the pyrrolidine to afford 15 mg of the title compound (34%).