Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:54][CH2:55][CH2:56][C:57](Cl)=[O:58]>O1CCCC1>[Cl:54][CH2:55][CH2:56][C:57]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:14]2[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]12)=[O:58]
Reactant: N#Cc1ncn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: N#Cc1ncn2c1N(C(=O)CCCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a stirred mixture of 4.5 g of 1,2-dihydro-4-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrimidine-8-carbonitrile (prepared as described in Example 2) and 3.6 g of [1,8-bis(dimethylamino)naphthalene-N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 120 ml of dry tetrahydrofuran at room temperature, under nitrogen was added over a period of 12-15 minutes a solution of 3.9 g of 3-chloropropionyl chloride in 30 ml of dry tetrahydrofuran. The mixture was stirred at room temperature under nitrogen for one hour then under reflux for 4 hours. The solution was filtered hot and the filtrate was evaporated to dryness in vacuo. The residue was triturated with anhydrous ether and gave 5.95 g of the product of the example as an off-white solid. The product was recrystallized from ethyl acetate, mp 165° 166° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.N([O-])=O.[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>Cl.O>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:25]=1
Reactant: Nc1ccccc1Sc1nc2ccccc2[nH]1
Reactant: COc1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccnc(-c2ccccc2Sc2nc3ccccc3[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 2-(1H-benzimidazol-2-yl thio)benzenamine (1.70 g) in dilute hydrochloric acid (11 ml) was added dropwise a solution of sodium nitrite (0.53 g) in water (5 ml), keeping the temperature below 0°. The reaction mixture was stirred at this temperature for 0.5 hours then added portionwise to a mixture of 4-methoxypyridine (42.40 g) and pyridine (0.57 g) stirring at 80° for 1 hour. The pyridines were distilled off, replaced with 880 ammonia which was in turn distilled off. The residue was treated with water, extracted into dichloromethane, washed, dried, evaporated and the residue was purified by flash column chromatography using ethyl acetate as eluant to give the sub-title product as a creamish foam, 0.20 g.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([OH:9])(=O)[CH3:7].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C#C.C#C.[Zn]>[CH:12]([C@@H:11]1[O:10][C@H:7]1[CH2:6][OH:9])=[C:13]=[CH:14][C:11]#[C:12][C:13]#[CH:14]
Reactant: CC(=O)O
Reactant: C1CCOC1
Agent: C#C
Agent: CS(=O)(=O)Cl
Agent: [Zn]
Product: C#CC#CC=C=C[C@@H]1O[C@H]1CO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a separate flask, the mesylate of 6-[(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol was prepared via the following procedure. To a stirred solution of 6-(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol (98 mg, 0.5 mmole), anhydrous lithium bromide (43 mg, 0.5 mmole) and a few milligrams of 1,10-phenanthroline in 5 ml of tetrahydrofuran at -78° C. was added n-butyllithium dropwise until a brown color was obtained (ca. 0.5 mmole of n-butyllithium). The mixture was stirred for one-half hour whereupon mesyl chloride (38 μl, 0.5 mmole) was added dropwise. The brown color discharged to yellow. The solution was stirred for 10 minutes at -78° C. and was then added all at once (via short teflon cannula and argon pressure) to the above stirred -20° C. solution of zinc diacetylene. The resultant mixture was stirred at -20° C. for 15 minutes and was then acidified by the addition of a solution of acetic acid in tetrahydrofuran. The mixture was then concentrated to ca. 1/4 volume and 30 ml of a mixture of ether-hexane 1:1 was added with stirring whereupon a gum separated. The supernatant was then filtered through a pad of silica gel. The filtrate was concentrated to dryness and immediately redissolved in a few ml of ether-hexane 1:5 (some solid did not dissolve). This solution of crude product was then purified via flash chromatography (LPS-1 silica gel, ether-hexane 1:10) to afford pure title compound (30 mg). This allene was stored in solution in ether-hexane in the freezer.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC([N:38]1[CH2:43][CH2:42][CH:41]([O:44][C:45]2[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:46]=2[F:53])[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:51][C:48]1[CH:49]=[CH:50][C:45]([O:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[C:46]([F:53])[CH:47]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2F)CC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCNCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 29.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-fluoro-4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (75 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17].C(N(CC)CC)C>CN1C(=O)CCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[OH:17])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Temperature: 200 °C

Procedure:
Morpholine (59.9 mg, 0.688 mmol) was added to a solution of 2-bromo-5-nitrophenol (100 mg, 0.459 mmol) and triethylamine (0.070 ml, 0.505 mmol) in NMP. The reaction mixture was heated via microwave irradiation to 200° C. for 1 h. The reaction was monitored by TLC. After completion of the reaction and following cooling, the solvent was removed in vacuo and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) to provide the title compound as a solid. 1H NMR: (CDCl3, 400 MHz): δ 7.82-7.79 (m, 2H), 7.20 (m, 1H), 6.69 (bs, 1H), 3.89 (m, 4H), 2.95 (m, 4H). ESI-MS: 225.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[NH:14][C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[Na].[CH3:30]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.CO>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH3:30])[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(CCCNC(=O)c2[nH]c(-c3ccccc3)c3cc(Cl)ccc23)OCCO1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(C(=O)NCCCC2(C)OCCO2)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide in 160 ml. of dimethylformamide is treated under an atmosphere of argon at 0°-5° C. with a solution of 2.1 g. of sodium in 40 ml. of methanol. The mixture is then stirred at room temperature for 30 minutes and subsequently added dropwise to a solution of 18.6 g. of p-toluenesulfonic acid methyl ester in 20 ml. of dimethylformamide. The mixture is subsequently stirred at room temperature for 30 minutes and then at 80° C. for 1 hour. After cooling, the mixture is poured on to 400 ml. of ice-water and, after the addition of 20 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue obtained is chromatographed on 500 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The uniform fractions are combined and evaporated, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide having a melting point of 137°-139° C. Recrystallization from ethanol yields colorless crystals of the same melting point.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:3]=1
Reactant: Ic1n[nH]c2ncccc12
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(I)c2cccnc21
Yield: 83.1 %

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-b]pyridine (9.8 g, 40 mmol, 1 equiv) and potassium carbonate (27.6 g, 5 equiv) in 15 mL of DMF at 90° C. was added ethyl chloroacetate (8.5 mL, 40 mmol, 1 equiv). Two hours later, the reaction mixture was diluted with ethyl acetate followed by washing with saturated aqueous NaHCO3. The organic layer was dried and concentrated to provide the crude product. Purification of the crude product by flash chromatography gave ethyl (3-Iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetate (11 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH2:12][C:13]([NH2:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][CH2:12][C:13]([CH3:15])([NH2:16])[CH3:14]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(N)CN
Solvent: c1ccncc1
Product: CC(C)(N)CNc1nc2ccccc2s1

Procedure:
A solution of 2-chlorobenzothiazole (5.0 g) in 1,2-diamino-2-methylpropane (20 ml) and pyridine (2.3 ml) was stirred 2 h at RT. The solvent was evaporated. Flash chromatography (silica gel; CH2Cl2/MeOH) provided 6.2 g of a colorless oil, which crystallized upon standing.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[NH2:29][CH2:28][CH2:27][NH:30][C:15]1[C:16]([Cl:18])=[C:17]2[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:26])=[CH:4][C:5]=2[F:25])=[CH:13][C:14]=1[F:20]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NCCNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Yield: 65.2 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), ethylenediamine (16 mg) and triethylamine (70 mg) were added to acetonitrile (5 ml), and the mixture was heated under reflux for 2 hours. After the reaction mixture was allowed to cool, deposits were collected by filtration. The deposits were washed successively with ethanol and diethyl ether to obtain the title compound (72 mg) as a pale yellow powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:22])[CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.CI>C1COCC1>[CH3:13][O:14][C:15](=[O:22])[CH:16]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[CH3:1]
Reactant: COC(=O)Cc1ccsc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccsc1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Anhydrous diisopropylamine (24.3 g) was added to Anhydrous THF (100 ml) which was then cooled by a dry ice-acetone bath. To this solution was first added dropwise n-butyllithium (15% w/o % in Hexane, 147 ml), then in a second step a THF solution (50 ml) of 3-thiophene acetic acid methyl ester (31.2 g). Thereafter, this solution was kept at the same temperature under cooling, while stirring was continued for 30 minutes. Then, methyl iodide (36.9 g) was added in one portion to the reaction mixture which after 30 minutes, was removed from the cooling bath to be allowed to reach to room temperature. After the reaction, THF was distilled off under reduced pressure and the formed residue was dissolved in water which was extracted by two portions of 200 ml ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by distillation to obtain 26.6 g 2-(3-thienyl)propionic acid methyl ester with bp 90°-92° C.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[ClH:1].[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C@H:10]3[C@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[CH2:11]3)=[CH:18][C:19]=2[O:25]1
Reactant: Oc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCOc1ccc([C@@H]2CCN(CCCCC)C[C@H]2COc2ccc3c(c2)OCO3)cc1

Procedure:
was prepared by refluxing 4-(4-hydroxyphenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride (0.35 g) with 1-bromopentane (1.8 ml) and K2CO3 (1 g) in abs. ethanol (25 ml) for 2 h. The rinse-up procedure described in example 1 gave the title compound. M.p. 148.2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:17](Cl)(Cl)=[O:18]>O1CCOCC1>[N:11]1([C:8]2[CH:7]=[C:3]3[C:2](=[CH:10][CH:9]=2)[NH:1][C:17](=[O:18])[NH:6][C:4]3=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2cc(N3CCCCC3)ccc2[nH]1
Yield: 91 %

Procedure:
2-Amino-5-piperidin-1-yl-benzamide (210 mg, 2.33 mmol) in dry dioxane (50 mL) was treated with 2N phosgene solution (1.28 mL in toluene). The resulting orange precipitate was heated to 80 C to give after 3 h, a pale yellow solid. The solution was cooled in an ice bath and the product was collect by filtration to give 6-Piperidin-1-yl-1H-quinazoline-2,4-dione 525 mg (91% yield) HPLC tr=3.6 min (85%), LCMS m/e 246.2 (M+H).
Reaction SMILES: COC1C=C(N2CCP(C)(=O)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][P:44]([CH3:48])(=[O:47])[CH2:43][CH2:42]3)=[CH:37][C:36]=2[O:49][CH3:50])[C:31]([Cl:51])=[CH:30][N:29]=1.[S:52]1[CH:56]=[CH:55][CH:54]=[C:53]1[CH2:57][NH2:58]>>[Cl:51][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][P:44]([CH3:48])(=[O:47])[CH2:43][CH2:42]3)=[CH:37][C:36]=2[O:49][CH3:50])=[N:33][C:28]([NH:58][CH2:57][C:53]2[S:52][CH:56]=[CH:55][CH:54]=2)=[N:29][CH:30]=1
Reactant: NCc1cccs1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline with 2,4,5-trichloropyrimidine generating 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine. 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine is then reacted with 1-(thiophen-2-yl)methanamine as described in Example 32.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenol (0.162 g, 0.495 mmol) was reacted with K2CO3 (0.089 g, 0.643 mmol) and methyl bromoacetate (0.098 g, 0.643 mmol) in acetone (5 ml) to give the product (0.161 g, 0.403 mmol, 81%) as an off-white solid, mp 113-117° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.67 (s, 3H), 3.70 (s, 3H), 4.06 (s, 2H), 4.80 (s, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.08-7.11 (m, 1H), 7.19-7.24 (m, 4H), 7.29 (dd, J=1.7, 8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.9 Hz, 2H), 7.56 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: Oc1ccc(-c2ccc(Cl)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cn3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-chloro-pyridin-2-yl)-phenol (Preparation 17) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a white solid (63 mg, 30%)
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[CH2:4].C(O)(=[O:21])C.O>[O-2].[Cr+6].[O-2].[O-2].C(Cl)Cl>[CH3:5][C:2]1([CH3:1])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[O:18][C:4](=[O:21])[CH2:3]1
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a soultion of borane-dimethyl sulfide complex (0.409 mL, 0.00460 mol) in methylene chloride (6.00 mL, 0.0936 mol) was slowly added a solution of tert-butyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (3.20 g, 0.0125 mol) in methylene chloride (6.00 mL, 0.0936 mol) with stirring at rt. After 2 h, the reaction mixture was slowly added to a solution of chromium(VI) oxide (7.52 g, 0.0752 mol) in acetic acid (45.00 mL, 0.7915 mol), and water (5.00 mL, 0.278 mol) at 5° C. After stirring the reaction mixture at rt for 12 h, water (60 mL) and methylene chloride (30 mL) were added. The organic layer was seperated and the aqueous layer was further extracted with methylene chloride (2×30 mL). The organic layers were combined, washed with brine (2×30 mL), dried and concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the product. LCMS (M+Na) 292.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:51])[C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:74]1([CH:79]2[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]2)[CH2:78][CH2:77][CH2:76][CH2:75]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:51])[C:42]2[CH:50]=[CH:49][C:45]([C:46]([N:82]3[CH2:83][CH2:84][CH:79]([N:74]4[CH2:78][CH2:77][CH2:76][CH2:75]4)[CH2:80][CH2:81]3)=[O:47])=[CH:44][CH:43]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-terephthalamic acid (0.56 mmol) was treated with dichloromethane (8 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 1.3 eq), 1-hydroxybenzotriazole (98 mg, 1.3 eq) and 4-pyrrolidin-1-yl-piperidine (113 mg, 1.3 eq). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with brine and with a saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and evaporated to dryness affording the crude title compound that was used as such for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[OH:18])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[O:18][C:9]2=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-chlorophenyl)(2-hydroxycyclohexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 mmol), benzotriazol-1-yloxytris(dimethylaminop)phosphonium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield 0.97 g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one as a clear oil. HRMS: calcd for C14H15ClO2+H, 251.0861; found (ESI, [M+H]+), 251.0844.