Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:19])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(=O)c(C(C)=O)c[nH]c12
Product: COc1cccc2c(Cl)c(C(C)=O)cnc12

Procedure:
3-Acetyl-8-methoxy-4(1H)-quinolone (4.23 g, 19 mmol) and phosphorus oxychloride (150 ml) were heated under reflux for 45 minutes, evaporated to small volume in vacuo, poured onto ice, and the mixture adjusted to pH 4 with sodium bicarbonate. Extraction with chloroform, drying and evaporation of the organic solution gave crude 3-acetyl-4-chloro-8-methoxyquinoline as a dark coloured oil (7.9 g), which was used without purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
Oxalyl chloride (0.053 mL, 0.6 mmol) was added to a stirred solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoic acid (WO 2005058848; 68 mg, 0.3 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen, and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow oil (ca 80 mg) which was used crude in the subsequent reaction (D46).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[C:34]([OH:36])=[O:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=1)=[O:17])[CH2:9]2
Reactant: Nc1ccc(-c2ccc(NC(=O)C(=O)O)cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(O)C(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
300 mg (2.14 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 300 mg (1.43 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 180 mg (0.71 mmol) of [(4′-aminobiphenyl-4-yl)amino](oxo)acetic acid [CAS Registry No. 100872-66-0] in 11 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., the reaction mixture is concentrated in vacuo, and the residue is dissolved in water and acetonitrile and purified by preparative HPLC. The concentrated product fractions are mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 64 mg (20.3% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][OH:36].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][OH:36])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCO)C1
Yield: 55 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-amino-ethanol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (60 mg, 55%); LCMS (method B): RT=3.25 min, M+H+=490.
Reaction SMILES: O=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([CH:10]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH3:26]>>[CH2:12]([C:2]1[NH:26][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCC(=O)CC(C=O)C(=O)OCC
Reactant: N
Product: CCCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Yield: 90 %

Procedure:
To 4.13 g (12 mmol) of the resulting ethyl γ-keto-α-formyloctadecanoate was added 150 ml of an ammonia-saturated ethanol solution and the mixture was then heated under reflux for 14 hours. After removing the solvent under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain 3.53 g (90% yield) of ethyl 5-tetradecylpyrrole-3-carboxylate, m.p. 59°-62° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[O:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:25][C:23](=[O:24])[C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[O:11])[CH:4]=2)[CH:19]=[N:20][CH:21]=1
Reactant: C#Cc1cccc(NC(=O)c2cccs2)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cccs3)c2)c1)c1ccccc1
Yield: 31.2 %

Procedure:
In a manner similar to that described in Example 449, thiophene-2-carboxylic acid (3-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (44 mg, 0.092 mmol, 31%).
Reaction SMILES: O=[N:2][C:3](=O)[C:4](=O)[C:5]1[NH:6]C2C(=CC=1)C=CC1=NC=CC=21.C1(C)[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1(C)C=CC=CC=1>[N:2]12[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26]=[N:6][CH2:5][CH2:4][CH2:3]2
Reactant: Cc1ccccc1C
Reactant: O=NC(=O)C(=O)c1ccc2ccc3nccc3c2[nH]1
Solvent: Cc1ccccc1
Product: C1=NCCCN2CCCCC12

Procedure:
The formula (XXXVI) 2-(2-imidazolin-2-yl)quinolinecarboxylate esters can also be prepared from a formula (XXXVIII) dioxopyrroloquinoline acetamide, wherein R1, R2, X, L, M, Q and R7 are as described above, by cyclization thereof with a strong base, such as 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) in the presence of an inert organic solvent such as xylene or toluene to give the crude imidazopyrroloquinolinedione of formula (XXXVII). The reaction mixture is heated to a temperature between 100° C. and 150° C., and water removed from the reaction mixture using a Dean-Stark water separator. At least one equivalent of alcohol R3OH represented by formula (V); wherein R3 is a substituent as described above, but excluding hydrogen and salt-forming cations, is then added to the reaction mixture, and the thus prepared mixture heated to reflux at a temperature between 100° C. and 150° C. to yield the formula (XXXVI) ester. The reaction may be graphically illustrated as follows: ##STR37## wherein R1, R2, R3, X, L, M, Q and R7 are as described above.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].NC(N)=O.[CH3:9][C:10]1([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1>>[CH3:9][C:10]1([CH3:20])[C:18]2[C:13](=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: NC(N)=O
Product: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A mixture of nitric acid (90% fuming, 35 mL) and urea (0.17 g) was cooled to -10° C. and purged with air for 20 minutes; 3,3-dimethyl-1-indanone (8.68 g, 54.2 mmoles) was added and the reaction was stirred for two hours at -10° C. to 5° C. The reaction mixture was poured into ice/H2O and extracted with ethyl acetate. The combined extracts were washed with distilled H2O, saturated NaHCO3 solution, saturated NaCl solution, and dried over MgSO4. The solvent was recovered under vacuum to obtain 10.0 g of a yellow solid. The crude product was recrystallized from methanol in two crops to obtain 8.08 g (71%) of the title D compound as yellow needles. MS: M- @ 205.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[OH-].[Na+].O.Cl>C(O)C>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc(Cl)c2ccccc2c1O
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 9.23 g of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (33 mmol), 90 ml of 2.5N aqueous sodium hydroxide solution, water (20 ml) and ethanol (110 ml) was refluxed with stirring for 2 h. Then the pH of the mixture was adjusted to 2 by the addition of concentrated aqueous hydrochloric acid. During the addition, the temperature of the mixture was kept at 20° C. by cooling with an ice bath. Stirring was then continued for 1 h before the solid component was separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85° C. to give a white powder. 6.64 g of the title compound were obtained; MS-(+)-ion: M+1=224.1 amu.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH2:15])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:23](Cl)=[O:24]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH:15][C:23](=[O:24])[C:22]3[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:20]([O:19][CH3:18])[CH:21]=3)[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3cc(OC)cc(OC)c3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid ethyl ester (compound A1) and 3,5-dimethoxy benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:20]2N(O)N=[N:23][C:21]=2[CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(N)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:23][CH:21]1[CH2:22][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 369.9 %

Procedure:
To a mixture of (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6 g, 26 mmol), HOBt (0.8 g, 6 mmol) and DCC (5.97 g, 29 mmol) in DCM (260 mL) was added cyclopropylamine (2.1 mL, 31 mmol) and DIPEA (6.8 mL, 39 mmol). The mixture was stirred at rt for overnight. The insolubles were filtered off, the filtrate was concentrated and extracted into ethyl acetate. The organic layer was concentrated and dried to give 6 g of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:28])([F:27])[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[F:28][C:13]([F:27])([F:12])[S:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1ccccc1-c1ccccc1
Solvent: ClCCl
Product: O=S(c1ccccc1-c1ccccc1)C(F)(F)F
Yield: 97.8 %

Procedure:
Under ice cooling, 7.77g (31.5 mmol) of m-chloroperbenzoic acid was added little by little to a solution of 7.63 g (30 mmol) of 2-(trifluoromethylthio)biphenyl in 20 ml of methylene chloride with stirring. The mixture was stirred overnight at room temperature. The precipitate in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give 7.93 g (97.8%) of 2-(trifluoromethylsulfinyl)biphenyl. The properties of the product were as shown below.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)([OH:3])=O.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:3])[NH:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[CH:17][CH:16]=1
Reactant: COCCCCc1ccccc1N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Product: COCCCCc1ccccc1NC(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 3a, 0.537 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.296 g of 2-(4-methoxybutyl)phenylamine are reacted. The title compound is obtained as a yellow oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=5.98.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]4)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: ClCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
2.11 g of methyl 6-hydroxy-2-naphthoate and 0.84 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 50 ml of DMF. 4.6 g of 4-(p-chlorophenyl)piperazinoethyl chloride are then added and the reaction mixture is stirred at 40° C. for 8 h. It is diluted with 350 ml of methanol and the precipitate which is deposited is filtered off with suction. It is dissolved in 80 ml of DMF and 10 ml of water, and the mixture is treated with 3.8 g of KOH and stirred at 100° C. for 10 h. The DMF is largely stripped off on a rotary evaporator, the residue is poured onto water and acidified, and the resulting precipitate is filtered off with suction. 2.5 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]ethoxy}-2-naphthoic acid are obtained; m.p. 197-199° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[BH4-].[Na+].N.O>C(O)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:12]2[CH2:13][CH2:14][N:15]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][CH2:17]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C3CCCCC3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 ul, 0.35 mmol) and Ti(OPr-i)4 (0.17 ml, 0.58 mmol) was ultrasonicated for 1 hr and then stirred at rt overnight under a nitrogen atmosphere. The mixture was diluted with ethanol (5 ml) and followed by addition of NaBH4 (33 mg, 0.87 mmol). The resulting mixture was stirred for 12 hr at rt. 2N NH3.H2O was added to quench the reaction and the mixture filtered through celite. The filtrate was extracted with ethyl acetate several times and the combined organic phases washed with water and brine, and dried over Na2SO4. Concentration in vacuo and MPLC purification (0:100 to 100:0 EtOAc:Heptane eluting on silcal gel 60) gave the title compound (24 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(NC(C)C)(C)C.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([O:12][CH3:13])[CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc(F)c([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A mixture of 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), tetrakis(triphenylphosphine) -palladium(0) (38 mg) and copper (I) iodide (13 mg) in N,N-diisopropylamine (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−5/1) to give 5-fluoro-4-nitro-2-phenylethynylanisole (0.18 g). This material was dissolved in ethyl acetate (5 mL). To the solution was added 10% palladium-carbon powder (0.45 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−4/1) to give the title compound (87 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1>>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:42]=[N:41][C:40]([N:43]5[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]5)=[CH:39][CH:38]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (200 mg, 0.451 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (196 mg, 0.677 mmol). The product was collected as a white solid (92 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.64-8.67 (m, 1H) 8.60 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.03-8.09 (m, 2H) 7.84 (d, J=1.26 Hz, 1H) 6.89-6.99 (m, 1H) 5.89 (s, 1H) 5.27-5.35 (m, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.41-3.56 (m, 4H) 2.69-2.91 (m, 4H) 2.22 (s, 3H) 2.07-2.20 (m, 6H) 1.97-2.06 (m, 2H) 1.85-1.93 (m, 2H) 1.65-1.74 (m, 2H). LC-MS (ES) m/z=526.3 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[O:4][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH3:19])=[O:17])[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)oc1C
Yield: 42.7 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-fluoroacetophenone (13.4 g) and methyl acetoacetate (8.6 g) to give the title compound (7.4 g, 63%) as a yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].CC1C=CC=C(C)N=1.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C(Cl)Cl>[CH2:40]([O:39][C:37]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@H:28]([O:29][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:19]([O:21][CH2:22][C:23]([Cl:25])([Cl:24])[Cl:26])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:38])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a -78° C. solution of 3.75 g (5.47 mmol) (R,R)-5-{2-[[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester and 60 mL of CH2Cl2 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf. After stirring at -78° C. for 1.5 h, the reaction mixture was quenched with 50 mL sat. aq. NaHCO3 and warmed to room temperature. After extraction with 3×150 mL Et2O, the combined organics were washed with 1×200 mL sat. CuSO4, 1×200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf =0.31; 4/1 hexanes/EtOAc) as a gummy colorless solid; 1H NMR (300 MHz, CDCl3): δ-0.13-(-0.08) (m, 3H), 0.00-0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H), 2.60-2.75 (m, 1H), 2.77-2.96 (m, 1H), 3.00-3.31 (m, 2H), 3.77-4.00 (m, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, 1H), 6.60-6.85 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 790 (M+ +Na, 100), 768 (M+ +H, 20).