Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](Cl)(=[O:14])[C:11](Cl)=O.[OH2:16]>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:11][C:10]([OH:14])=[O:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O
Solvent: ClCCl
Product: O=C(O)CCc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
3-(4-Fluorophenyl)propanoic acid was prepared by procedures analogous to those of Example 6 from 4-fluorobenzaldehyde. Oxalyl chloride (25 mL, 36.4 g, 0.287 mol) was added to 20.0 g (0.119 mol) of this acid. The resulting slurry was heated at reflux with stirring for 1 hour. The solution obtained was cooled and the volatile components were removed by evaporation under reduced pressure. Dichloroethane was added and removed by evaporation under reduced pressure. The residue was dissolved in 75 mL of dichloroethane and the solution was added with stirring to a slurry of 16 g of anhydrous aluminum chloride in 75 mL of dichloroethane. The mixture evolved hydrogen chloride and exothermed raising the temperature to about 40° C. It was then heated at reflux with stirring for about 45 min after which it was allowed to cool overnight. Concentrated aqueous hydrochloric acid (100 mL) was then added with stirring, which resulted in a large exotherm. The resulting mixture was diluted with 100 mL of dichloromethane and 250 mL of water and the organic phase was recovered by means of a separatory funnel, washed with 300 mL of 0.5N aqueous sodium hydroxide, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue, which amounted to 16.3 g of cream colored solid melting at 57°-60° C., was the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][N:12]=[CH:13]3)=[CH:8][CH:7]=2)=[CH:2]1.Cl.[H][H]>ClCCl.C(O)C.[Pt]=O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13]3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: [H][H]
Reactant: c1cc2ccc(-c3ccsc3)cc2cn1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: c1cc(-c2ccc3c(c2)CNCC3)cs1
Yield: 63.5 %

Procedure:
A solution of 7-(3-thienyl)isoquinoline (0.15 g, 3 mmol) in dichloromethane was treated with an excess of HCl gas. The mixture was evaporated under reduced pressure to give a colourless solid. The solid was dissolved in ethanol, platinum oxide (100 mg) added, the reaction mixture hydrogenated at 50 psi on a Parr apparatus until uptake of hydrogen ceased. The catalyst was collected by filtration and the filtrate was hydrogenated again using fresh catalyst until the starting material had been consumed. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give crude 7-(3-thienyl)-1,2,3,4-tetrahydroisoquinoline as an oil (0.41 g, 62%). A mixture of this oil (0.40 g, 1.85 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.325 g, 1.85 mmol) in toluene (3 ml) was heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from toluene afforded the title compound (0.17 g, 28%), m.p. 228°-230° C.; (Found: C, 72.82; H, 5.46; N, 12.05. C21H19N3S requires C, 73.01; H, 5.54; N, 12.16%); δH (DMSO-d6) 2.72 (2H, t, J 5.4 Hz, CH2), 2.80 (2H, t, J 5 Hz, CH2), 3.59 (2H, s, CH2), 3.82 (2H, s, CH2), 7.02 (1H, dd, J 7.7, 4.7 Hz, 5-H), 7.11 (1H, d, J 8.0 Hz, ArH), 7.35 (1H, s, ArH), 7.42-7.50 (3H, m, ArH), 7.57 (1H, dd, J 5.1, 3 Hz, ArH), 7.76 (1H, s, ArH), 8.04 (1H, dd, J 7.7, 1 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1 Hz, 6-H), and 11.49 (1H, br s, NH); m/z (CI+, NH3) 345 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#CCCO)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCCCO)cc1
Yield: 92.9 %

Procedure:
A solution of 1,1-dimethylethyl 4-(4-hydroxy-1-butyn-1-yl)benzoate (0.9 g, e.g. which can be as prepared in Intermediate 22) in a mixture of ethanol (50 ml) and ethyl acetate (5 ml) was hydrogenated over platinum(IV) oxide (PtO2, 0.09 g, 10% w/w) for 18 hours at room temperature. The mixture was filtered through a bed of Celite, washing through with ethanol. The solvents were evaporated to dryness to give the title compound as a yellowy/brown oil (0.85 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.60 (14H, m), 1.70 (2H, m), 2.70 (2H, t, J=7.53 Hz & 7.78 Hz), 3.67 (2H, t, J=6.53 Hz & 6.27 Hz) 7.23 (2H, d, J=8.28 Hz), 7.91 (2H, d, J=8.03 Hz). Extra protons at about 1.5-1.6 ppm may perhaps be due to residual H2O in CDCl3. LCMS showed TRET=3.26 min with: MH+ not seen, and [MH]++18 adduct=268.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:5][CH:4]=1.[IH:16]>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCCCCBr)cc1
Reactant: I
Solvent: CC(=O)O
Product: Oc1ccc(CCCCCCI)cc1

Procedure:
A solution of 68 g. (0.25 mole) of 6-(4-methoxyphenyl)hexyl bromide in 500 ml. of glacial acetic acid was treated with 200 ml. of 50% aqueous hydriodic acid. The reaction was boiled at reflux for 5 hours. During the reflux period the condenser was removed briefly from time to time to allow methyl iodide to escape. The reaction was evaporated to dryness in vacuo. The residue was partitioned between water and ether. The organic phase was washed with water, then with dilute sodium thiosulfate until the iodine color was gone. The clear organic solution was evaporated in vacuo in a warm water bath to give a clear oil, 70 g. (92%) of 6-(4-hydroxyphenyl)hexyl iodide, which crystallized slowly after several days at room temperature.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)=[N:25][C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:32]3[CH:39]=[CH:38][C:35]([CH2:36][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:34][CH:33]=3)=[N:25][C:26]3[N:27]([CH:29]=[CH:30][N:31]=3)[CH:28]=2)=[CH:21][CH:22]=1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Fc1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)cc1
Reaction time: 1 h

Procedure:
95 mg (0.35 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 2.7 mL NMP. After addition of 0.1 mL triethylamine the reaction mixture is stirred for one hour. 100 mg (0.32 mmol) 4-[6-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-7-yl]-benzaldehyde and 0.03 mL acetic acid are added. The reaction mixture is stirred for three days at room temperature. 73 mg (0.35 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is treated with saturated NaHCO3 and stirred vigorously for one hour. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 90 mg (54%) of the desired product are obtained.
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:21][C:14]=23)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:21][C:14]=23)[CH2:11]1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CNC4)ncnc32)cc1
Yield: 318.5 %

Procedure:
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.01 mmol, 46 mg) was dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL). Palladium catalyst (30 mg, 65% by wt) was added to the reaction. The mixture was exposed to hydrogen gas for 60. minutes at room temperature and atmospheric pressure. The mixture was passed through celite to remove palladium catalyst. Removal of organic solvents in vacuo and purification by flash chromatography provided 4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (11 mg, 5%). 1H NMR (400MHz, MeOH-d4) δ (ppm): 8.45 (m, 2H); 8.37 (d, 2H); 8.05 (d, 2H); 4.54 (m, 1H); 4.35 (dd, 2H); 3.69 (m, 2H); 3.09 (s, 3H). LCMS (ESI), m/z 346.2 (M+H+, 100%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[CH3:15][N:16]([CH3:17])[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CNC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
To a solution of Boc-L-alanine (2.32 g, 12.26 mmol) in DCM (20 mL) was added dimethylamine hydrochloride (2 g, 24.5 mmol) and DIPEA (3.1 g, 24.53 mmol). The solution was kept at 0° C. for 10 min, then HOBt (3.31 g, 24.5 mmol) and EDCI (4.6 g, 24.5 mmol) were added. The mixture was stirred at room temperature for 10 h, and then poured into water (40 mL) and extracted with DCM (100 mL×3). The extracts was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (10-20% EtOAc in petroleum ether) to give Boc-L-alanine N,N-dimethyl amide as a colorless oil (1.1 g, 42%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H), 5.51 (brs, 1H), 4.56-4.63 (m, 1H), 3.03 (s, 3H), 2.93 (s, 3 H), 1.39 (s, 9H), 1.26 (d, J=6.8, 3 H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].C(O)(=O)C.[I:14]Cl>C(Cl)Cl>[I:14][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(N)n1
Reactant: ClI
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc(N)sc1I
Reaction time: 0.5 h

Procedure:
The above prepared 4-isopropyl-thiazol-2-ylamine (1.020 g, 7.17 mmol) was dissolved in 14 mL of CH2Cl2 and 2.8 mL of acetic acid and treated at 0° C. with iodine monochloride (7.53 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 0.5 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness yielded 1.922 g of the title compound as dark brown viscous oil, sufficiently pure to be used for the next step.
Reaction SMILES: F[C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+].CCCCC.[H][H]>O1CCOCC1.O1CCCC1>[CH:14]1([N:13]2[C:17]3[C:3](=[CH:2][C:20]([F:21])=[C:19]([F:22])[C:18]=3[F:23])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 50.9 %

Procedure:
To 2.0 g (6.0 mmol) of the 2-(2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylic acid, ethyl ester in 60 ml of dry dioxane was added 0.29 g of sodium hydride 50% dispersion) that was prewashed with pentane. The sodium hydride was delivered in 10 ml of dry tetrahydrofuran at 0° C. When evolution of hydrogen began to slow, the mixture was refluxed for two hours. It was concentrated, and the residue taken up in dichloromethane, which was water extracted, dried (MgSO4), and concentrated. The residue was purified by column chromatography (silica gel 70-200 mesh, using chloroform:hexane:isopropanol, 4:5:1) to give 0.95 g of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, mp 168-169° C. This material was dissolved in acetic acid at 100° C. and was treated with 10 ml of 0.5N hydrochloric acid for 2.5 hours. The mixture was cooled and water added. The solids were then collected to give 0.7 g of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid, mp 226-228° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[CH:4][CH:3]=1.[CH3:17][S:18]([CH2:21][C:22]1[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=[CH:25][N:26]=1)(=[O:20])=[O:19].[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: ClCc1coc(/C=C/c2ccc(Br)cc2)n1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Yield: 78.1 %

Procedure:
Using 2-[(E)-2-(4-bromophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (266 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (361 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1([F:29])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:19]=2[O:18]1>C(Cl)(Cl)Cl>[F:29][C:17]1([F:16])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([N:12]3[CH2:13][CH2:14][C:15]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=[N:9][C:10]=4[CH2:11]3)=[O:27])[C:19]=2[O:18]1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Reactant: c1ccc(-n2cnc3c2CCNC3)cc1
Solvent: ClC(Cl)Cl
Product: O=C(c1cccc2c1OC(F)(F)O2)N1CCc2c(ncn2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of the product of Example 50, Step A (28 mg, 0.141 mmol) and TEA (23 μL, 0.169 mmol) in CHCl3 (1 mL) cooled to 0° C. was added 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (34 mg, 0.155 mmol). The reaction was warmed to room temperature and stirred overnight. The crude reaction mixture purified on 12 g SiO2 column with 0-4% NH3/MeOH CH2Cl2 to give the desired compound (43 mg, 80%). MS (ESI): mass calcd. for C20H15F2N3O3, 383.1. m/z found, 384.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.71-7.39 (m, 4H), 7.36-7.09 (m, 5H), 4.88 (s, 1H), 4.58 (t, J=1.6 Hz, 2H), 4.08 (t, J=5.9 Hz, 2H), 3.66 (t, J=5.6 Hz, 1H), 2.86-2.74 (m, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=2)[NH:22][N:21]=1.[CH2:30]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][C:36](=O)[CH2:37]2)[CH2:31][CH3:32].N>ClC(Cl)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][CH:36]3[CH2:35][CH:34]4[N:33]([CH2:30][CH2:31][CH3:32])[CH:38]([CH2:39][CH2:40]4)[CH2:37]3)[CH:27]=2)[NH:22][N:21]=1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Reactant: CCCN1C2CCC1CC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCN1C2CCC1CC(Nc1ccc3[nH]nc(Br)c3c1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 1.1 %

Procedure:
Sodium triacetoxyborohydride (159 mg, 0.750 mmol) and then acetic acid (29 μl, 0.507 mmol) were added to a suspension of 3-bromo-1H-indazol-5-amine (106 mg, 0.500 mmol) and 8-propyl-8-azabicyclo[3.2.1]octan-3-one (100 mg, 0.598 mmol) in dichloroethane (3 ml), and the resulting mixture was stirred at room temperature for 1 day. Aqueous ammonia was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (chloroform/methanol/triethylamine=100/10/5) and a preparative thin-layer chromatography (200×200×0.5 mm, eluent: chloroform/methanol/triethylamine=100/5/5) to obtain 3-bromo-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (2 mg, 1%).
Reaction SMILES: [O:1]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:22][N:4]2[CH2:3][CH2:2][O:1][C:9]3[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=3[O:7][CH2:6][CH2:5]2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CS(=O)(=O)Nc1ccc2c(c1)OCCN(CC1CC1)CCO2

Procedure:
In a manner similar to example 4, react N-(3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonin-9-yl)methanesulfonamide with cyclopropanecarboxaldehyde and NaBH3CN to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[C:36]([CH2:38][C:39](O)=[O:40])#[N:37].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([C:39](=[O:40])[CH2:38][C:36]#[N:37])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: N#CCC(=O)O
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)N(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixture of ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.00 g), cyanoacetic acid (0.36 g) and methylene chloride (20 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.82 g) at room temperature. The reaction mixture is stirred overnight at room temperature, and then washed with 2% aqueous hydrochloric acid and brine. The organic layer is dried and evaporated to remove the solvent. The crude residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-5-cyanoacetyl-4,5,6,7-tetrahydroimidazo[4,5-c}pyridine-4-carboxylate (0.76 g) as white foam.
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[N:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C(C)=CC=CC=1.ClCCl>[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:5]=4[N:6]=3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc2oc(=S)[nH]c2c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Temperature: 130 °C

Procedure:
Methyl 2-thioxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (Example 94A, 300 mg, 1.43 mmol) and 1,4′-bipiperidine (483 mg, 2.87 mmol) were combined in xylene (2 mL). The mixture was heated in a microwave to 130° C. for 20 minutes. The reaction mixture was diluted with dichloromethane, washed with water, and the organic layer was absorbed on silica gel. The crude mixture was purified using silica gel chromatography (40 g column) eluting with a gradient of methanol/dichloromethane (3-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38-1.50 (m, 2 H) 1.54-1.72 (m, 5 H) 1.95 (d, J=12.89 Hz, 2 H) 2.46-2.59 (m, 6 H) 3.03-3.16 (m, 2 H) 3.91 (s, 3 H) 4.32-4.36 (m, 1 H) 4.36-4.41 (m, 1 H) 7.25 (d, 1 H) 7.79 (dd, J=8.48, 1.70 Hz, 1 H) 8.00 (d, J=1.70 Hz, 1 H); MS (ESI+) m/z 344.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C1CCNCC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCCCC1
Yield: 89 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperidine gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (232 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 3.74 (s, 3H), 3.18-3.12 (m, 4H), 1.74-1.63 (m, 6H)
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]1([C:17]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.CO>C1(C)C=CC=CC=1.ClCCl>[C:7]1([C:17]2([CH2:22][C:23]([NH2:1])=[NH:24])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC1(c2cccc3ccccc23)CCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N=C(N)CC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NH4Cl (2.659 g, 49.72 mmol) in dry toluene (80 mL) was added tri-methyl aluminum (2M in toluene, 25.0 mL, 49.72 mmol) slowly at 5° C. then warm to room temperature and stirred for 2 h. A solution of (1-naphthalen-1-yl-cyclopentyl)-acetonitrile (342) (3.9 g, 16.57 mmol) in toluene (5 mL) was added to the above reaction mixture and stirred for 18 h at 85° C. (reaction was monitored by LC-MS). The reaction mixture was cooled to 0° C. and quenched with a suspension of silica gel in chloroform and then stirred for 0.5 h at room temperature. After being filtered through a sintered funnel, the residue was washed well with methanol and the combined filtrate was concentrated under reduced pressure to get a crude mass. 10% methanol in dichloromethane was added to the residue, from which the insoluble material was again filtered off and the filtrate was concentrated in vacuum to get semi pure 2-(1-naphthalen-1-yl-cyclopentyl)-acetamidine; hydrochloride (343) (4.5 g) as a brown sticky mass. This raw product was used in the next step without purification.