Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([CH3:23])=[C:18]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:28]=[C:27]4[CH:39]=O)[CH:17]=2)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([CH3:23])=[C:18]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:37][CH2:38]3)[CH:28]=[C:27]4[CH2:39][N:4]3[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][CH2:9][OH:10])[CH2:2][CH2:3]3)[CH:17]=2)[CH2:12][CH2:13]1
Reactant: OCCN1CCCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(CCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1,4-Diazepan-1-yl)ethanol (311 mg) was added to a suspension of the product of Example 75 step i) (301 mg) in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour before the addition of sodium triacetoxyborohydride (457 mg). The reaction was then stirred at room temperature for 1 hour. The reaction mixture was treated with methanol (2 mL) and then concentrated to dryness. The resulting material was purified by HPLC then by SCX ion exchange chromatography (eluting with methanol followed by 1.5M methanolic ammonia). The fractions containing product were concentrated to dryness and the residue triturated with acetonitrile to afford the title compound as a solid (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@H]1CCCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:18][C@@H:14]2[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 38 %

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (xi), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) with (S)-2-methyl-piperidine to obtain 1.5 g (38% yield) of the title compound as a beige oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:31])([F:30])[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:22]4[CH:23]=[N:24][C:19]([C:18]([F:17])([F:30])[F:31])=[CH:20][CH:21]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)CCc3ccc(C(F)(F)F)nc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-[6-(trifluoromethyl)-3-pyridyl]propionic acid, the title compound was obtained as white solid.
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: CCOC(C)=O
Solvent: CC(C)NC(C)C
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:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13]
Reactant: C#CCCCO
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCC#Cc1ccccn1
Yield: 54.7 %

Procedure:
As in example 1, 15.8 g of 2-bromopyridine and 8.4 g of 4-pentyn-1-ol were reacted together in 125 mL of dichloromethane in the presence of 4.2 mL of triethylamine, 2.1 g of bis(triphenylphosphine)palladium dichloride and 0.135 g of cuprous iodide. After 48 hours at reflux, the reaction was worked up in the usual manner. Distillation of the crude product yielded 8.8 g of 5-(2-pyridinyl)-4-pentyn-1-ol (bp 115°-120° C./0.25 mm).
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>CCO.O>[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(NN)cc1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=O)[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6].CO>O.[OH-].[Na+]>[CH2:4]([C:8]1[CH:13]=[C:12]([C:14](=[N:2][OH:3])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: NO
Reactant: CC(=O)c1cc(C)nc(CC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc(C)nc(CC(C)C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of hydroxylamine hydrochloride (120 mg, 1.732 mmol) in water (0.5 mL) and 1 N aq. NaOH (1.2 mL) is added to 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone (276 mg, 1.44 mmol). The solution is stirred at 80° C. for 2 h and MeOH is added to maintain homogeneity of the mixture. The mixture is cooled to rt and the precipitate that forms is collected, washed with water and dried in vacuo to give 1-(2-isobutyl-6-methyl-pyridin-4-yl)-ethanone oxime (258 mg) as a white solid; 1H NMR (D6-DMSO): δ 0.88 (d, J=6.5 Hz, 6H), 1.98-2.10 (m, 1H), 2.13 (s, 3H), 2.45 (s, 3H), 2.56 (d, J=7.0 Hz, 2H), 7.22 (s, 1H), 7.27 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([C:57]3([NH2:63])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C>[Cl:49][C:50]1[CH:65]=[CH:64][C:53]2[NH:54][C:55]([C:57]3([NH:63][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[C:2]([CH3:1])[CH:3]=4)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC1(c2nc3cc(Cl)ccc3[nH]2)CCCCC1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC2(c3nc4cc(Cl)ccc4[nH]3)CCCCC2)ccc1C(=O)N1CCCC1
Yield: 78 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)cyclohexylamine in tetrahydrofuran. Yield: 78%; Rf value: 0.28 (silica gel; ethyl acetate); C26H29ClN4O2 (464.99); mass spectrum: (M+H)+=465/467 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNc1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.116.1, starting from 4-chloroaniline and ethyl acrylate, ethyl N-(4-chlorophenyl)-3-aminopropionate was obtained as light tan oil.
Reaction SMILES: [Na].[CH:2]1[C:7]([CH:8]=O)=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17]>C(O)C>[CH2:11]1[O:12][C:4]2[CH:3]=[CH:2][C:7]([CH:8]=[C:15]([CH2:14][C:13]([OH:22])=[O:21])[C:16]([OH:18])=[O:17])=[CH:6][C:5]=2[O:10]1
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: CCO
Product: O=C(O)CC(=Cc1ccc2c(c1)OCO2)C(=O)O

Procedure:
Dissolving 19.14 g of metal sodium in 400 ml of ethanol, 110.8 ml of diethyl succinate and 100 g of piperonal were added, and the solution was heated and refluxed for 3 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in 700 ml of water, and washed with 300 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 300 ml of diethyl ether. The diethyl ether layer was washed once with saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dissolved by 181.4 g in 350 ml of ethanol, and 400 ml of 5N sodium hydroxide was added to stir overnight at room temperature. The reaction solution was concentrated in vacuo, and the residue was washed with 200 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 400 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate anhydride, and concentrated in vacuo. To the obtained residue, 300 ml of diethyl ether was added to solidify, and the captioned compound was obtained. Yield: 67.34 g.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]([C:29]1[C:37]2[C:32](=[CH:33][C:34](Br)=[CH:35][CH:36]=2)[N:31]([CH3:39])[CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[CH3:25][O:26][C:27]([C:29]1[C:37]2[C:32](=[CH:33][C:34]([N:22]3[CH2:23][CH2:24][CH:19]([O:18][CH2:17][C:5]4[C:6]([C:9]5[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=5[Cl:15])=[N:7][O:8][C:4]=4[CH:1]4[CH2:2][CH2:3]4)[CH2:20][CH2:21]3)=[CH:35][CH:36]=2)[N:31]([CH3:39])[CH:30]=1)=[O:28]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Temperature: 120 °C
Yield: 43.3 %

Procedure:
A 250 mL sealed round bottom flask under nitrogen is charged with 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine (15 g, 40.84 mmol), 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (15.33 g, 57.18 mmol); potassium carbonate (11.29 g, 81.68 mmol), copper(I) iodide (3.11 g, 16.34 mmol), and proline (1.88 g, 16.34 mmol) in 80 mL of dimethyl sulfoxide. The reaction mixture is heated at 120° C. for 16 h. Then, it is cooled down to room temperature, quenched with water (200 mL) and extracted with EtOAc (3×150 mL). The organics are washed with water and brine, dried over MgSO4, filtered and evaporated. The crude is purified by flash silica gel chromatography using hex/EtOAc 8:2 to 1:1 as eluent system, to obtain 9.8 g of the title compound as a white solid (43%). MS (m/e): 554 (M+1)
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2Cl)cc1

Procedure:
Compound (99) was prepared from compound (20) and (2-chlorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.86 mins, m/z (ES−)=341 and 343 (M−H for C19H15ClO4).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[O:18].CN([CH:36]=[O:37])C>CCCCCC.C(OCC)C>[F:13][C:14]1[C:15]([CH:36]=[O:37])=[C:16]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:22])=[O:18]
Reactant: CN(C)C=O
Reactant: CC(C)N(C(=O)c1cc(F)cc(C(F)(F)F)c1)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)N(C(=O)c1cc(C(F)(F)F)cc(F)c1C=O)C(C)C
Temperature: -75 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A dried 200 ml round-bottomed flask containing 20 ml diethylether was cooled to −75° C. then 22.15 mmol diisopropylamine, 22.15 mmol 1.6M n-butyllithium in hexane, and a solution of 14.77 mmol 3-fluoro-N,N-diisopropyl-5-trifluoromethyl-benzamide in 20 ml diethylether were added sequentially. The mixture was stirred at −75° C. for 2 hours. 2.9 ml DMF was added dropwise. After the reaction was stirred for another hour, the mixture was warmed and stirred at room temperature for 30 minutes. The mixture was quenched with 100 ml 10% citric acid and extracted 3 times with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (90% yield). MS (m/e): 320.1 (M+H+, 100%)
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.CO.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:1][C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=4[C:4]=3[N:3]=2)=[CH:23][CH:22]=1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(N)ncc1CC2
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (244 mg, 1.0 mmol) in a mixture of glacial acetic acid/methanol/water (1:1:1) (30 mL) in a round-bottom flask were added p-methoxybenzaldehyde (0.44 mL, 450 mg, 3.0 mmol) and then 85% sodium cyanoborohydride (210 mg, 2.0 mmol). The solution was stirred at room temperature for 7 hours. At that time further amount of aldehyde (0.44 mL) and sodium cyanoborohydride (210 mg) were added and stirring was continued overnight. The reaction mixture was poured into ice-water (200 mL), the pH was adjusted to 10 by addition of saturated sodium carbonate and the solution extracted with ethyl acetate (4×20 mL). The collected organic extracts were washed with brine until neutral, with water and dried over Na2SO4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)=[O:4].[OH-].[Na+].CO.O>C1COCC1>[C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[N:10]([CH3:14])[CH:9]=2)=[CH:21][CH:20]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(NC(=O)c3ccccc3)cc1)cn2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (69 mg, 0.17 mmol), sodium hydroxide (21 mg, 0.52 mmol), methanol (3 mL), water (1 mL) and THF (3 mL) was heated to 60° C. for 24 hr. The reaction solution was then cooled to room temperature and concentrated in vacuo. The remaining residue was diluted with ethyl acetate (20 mL) and washed with 1N HCl (20 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid (64 mg, 98% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)=[C:10]([C:20](OC)=[O:21])[C:9]=2[C:24](OC)=[O:25])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[NH4+].[OH-]>ClCCl.CCOCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)=[C:10]([CH2:20][OH:21])[C:9]=2[CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: OCc1c(CO)c2sc3ccccc3n2c1-c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
A solution of dimethyl 1-(4-fluorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate (2.4 g, 6.6 mmol) in anhydrous dichloromethane (30 mL) was added dropwise to a stirred mixture of lithium aluminum hydride (0.6 g, 16.0 mmol) in anhydrous ether (20 mL) at −5° C. to 0° C. The reaction mixture was allowed to stir at this temperature for 20 min. The excess hydride was decomposed by adding water (1 mL) followed by NH4OH (1 mL) and water (1 mL) at −5° C. to 0° C. The mixture was filtered through a pad of Celite, washed with several times with dichloromethane. The combined filtrate and washings were washed successively with water and brine solution. The organic layer was dried (Na2SO4) and concentrated to dryness in vacuo. The residue was triturated with ether to give (1-(4-fluorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-diyl)dimethanol (BO-1592), 1.5 g (76%); mp 155-156° C. 1H NMR (DMSO-d6) δ 4.22 (2H, d, J=5.1 Hz, CH2), 4.66 (2H, d, J=5.1 Hz, CH2), 4.73 (1H, t, J=5.1 Hz, exchangeable, OH), 5.13 (1H, t, J=5.1 Hz, exchangeable, OH), 6.83-6.85 (1H, m, ArH), 7.15-7.19 (2H, m, 2×ArH), 7.37-7.41 (2H, m, 2×ArH), 7.53-7.57 (2H, m, 2×ArH), 7.79-7.81 (1H, m, ArH). Anal. Calcd. for (C18H14FNO2S): C, 66.04; H, 4.31; N, 4.28; S, 9.79. Found: C, 65.25; H, 4.22; N, 4.14; S, 9.76.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH2:34][CH2:35][Cl:36].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]([CH2:33][CH2:34][CH2:35][Cl:36])[C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)n(CCCCl)c2c1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxylate (140 mg, 0.331 mmol) and 1-bromo-3-chloropropane (156 mg, 0.994 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydride (17 mg, 0.430 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl-1H-indole-6-carboxylate (167 mg, yield 100%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[OH-].[Li+]>C(O)C>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][CH3:19])([C:4]([OH:20])=[O:3])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 45.3 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-ethylisonipecotic acid ethyl ester (570 mg) in ethanol (10 ml) was added a 1M lithium hydroxide solution (8 ml), and the mixture was refluxed under heating for 20 hours. Then, the reaction mixture was concentrated, and water was added to the residue. The aqueous layer was washed with ether, acidified with 1N hydrochloric acid, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (233 mg, yield 45%).