Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.CO>[CH2:18]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCc1ccc(NCc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 4-(N-Boc-2-aminoethyl)aniline 28 (10 g, 42.34 mmole), benzaldehyde (4.52 mL, 44.47 mmole), and molecular sieves 4A (10 g) in toluene (100 mL) was refluxed at 95° C. for 15 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and NaCNBH3 (2.79 g, 44.4 mmole) were added. The reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash silica column chromatography: 1/1 hexane/EtOAc gave N-benzyl4-(N-Boc-2-aminoethyl)aniline 41 as colorless oil (11.5 g, 83%). Rf=0.75 in 1/1 hexane/EtOAc. H1-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.38-7.2 (m, 5H), 6.87-6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H), 1.41 (s, 9H); ESMS (C20H26N2O2): calcd. 326.4, obsd. 328 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:16][NH:17][O:18][CH3:19].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)acetic acid (1 g, 5.1 mmol), N,O-dimethylhydroxylamine hydrochloride (480 mg, 5.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (978 mg, 5.1 mmol), hydroxybenzotriazole (690 mg, 5.1 mmol) and triethylamine (2.57 g, 25.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8:1) to afford 2-(3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (370 mg, yield 30.3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]([O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C)Oc2ccccc2-n2cccc21

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (5 g), described in Example 1, ethyl acetoacetate (4.3 g) and p-toluenesulfonic acid (0.5 g) in benzene (1,500 ml) is stirred and heated at reflux with a Dean-Stark water trap for 3 hr. Ethyl acetoacetate (1.0 g) is added and the reaction mixture kept under the refluxing condition overnight. After being cooled, the mixture is washed with a 5% solution of sodium bicarbonate and then water. The benzene solution is dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on a column of silica gel. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-acetic acid ethyl ester (3; R1 and R2 = H,R3 = CH3, n = 1, X = 0 and A = COOC2H5), νmaxCHCl3 1,725, 1,600, 1,505, 1,345, 1,080, 1,031 cm-1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.O>C1(C)C=CC=CC=1>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a suspension of potassium carbonate (7.78 g, 56.3 mmol, 1.10 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (15.00 g, 51.16 mmol) in toluene (50 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)-pyrazole-3-carbonyl chloride (17.62 g, 51.15 mmol, 1.000 equiv.) in toluene (55 mL) at 60° C. After 1.5 h at this temperature, the mixture was cooled and water was added. The resulting precipitate was collected by filtration, washed with water and petrol ether and dried to obtain the title compound (18.73 g, 65%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O.C(O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][OH:3])=[CH:14][CH:13]=1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
Add hydroxylamine hydrochloride (0.379 g, 5.458 mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2 mL) to a solution of 4-(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL). Heat the mixture at 80° C. for 2 h. Cool to ambient temperature and remove the solvent in vacuo. Partition the residue between EtOAc and water. Separate and dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to obtain the desired intermediate (311 mg, 58%). GC-MS m/z: 198 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.O1CCCC1>O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:17][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A mixture of 2.0 g 3-nitrobenzene sulfonyl chloride, 1.8 g cyclopropyl amine and 50 mL tetrahydrofuran was stirred for 30 minutes under ice-cooling. Water was added to the mixture which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, then the residue was dissolved in 100 mL solvent mixture of tetrahydrofuran and methanol, 50 mg of 10% palladium-carbon was added thereto, and the mixture was hydrogenated at ordinary pressure for 12 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated, whereby 1.5 g of the title compound was obtained as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1.[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[OH:2][C:3]1[N:7]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:13])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1
Reactant: COc1c(-c2ccnc(C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
Combined 6-(5-methoxy-4-(2-methylpyridin-4-yl)-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (25.8 mg, 0.063 mmol) and lithium chloride (13.42 mg, 0.317 mmol) in DMA (0.5 mL) and then heated at 50° C. using a heating block for 2 days. Additional portion of lithium chloride (13.42 mg, 0.317 mmol) was added and the reaction mixture was stirred at 100° C. for 17 hours. The reaction mixture was cooled to 23° C., filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 10-40% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give a residue. The residue was dissolved in DMSO, filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO, and purified again via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using an isocratic method of 17% ACN (with 0.05% TFA) in water (with 0.05% TFA) to give the title compound, as a TFA salt, (6.2 mg, 19.30% yield) as a green oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.26 (m, 2H) 1.55-1.67 (m, 2H) 1.77-1.84 (m, 1H) 2.51 (br. s., 3H) 3.17-3.24 (m, 2H) 3.24-3.32 (m, 2H) 3.83-3.88 (m, 2H) 7.77-8.07 (m, 2H) 8.07-8.22 (m, 1H) 8.22-8.30 (m, 1H) 8.36-8.44 (m, 1H) 8.58-8.67 (m, 1H) 8.67-8.81 (m, 1H) 8.81-8.92 (m, 1H) 13.58 (br. s., 1H). MS m/z [M+H]+ 394.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:27])=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxy-5-trifluoromethylbenzoic acid (8.10 g), toluene (160 mL), N,N-dimethylformamide (5 droplets) and thionyl chloride (4.80 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and then used for the synthesis of (i).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:22]([NH:24][NH2:25])=[O:23])=[N:14][C:15]3[N:16]([N:19]=[CH:20][CH:21]=3)[C:17]=2[F:18])=[C:7]([F:26])[CH:6]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[O:23][C:22]([C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([Br:4])=[CH:6][C:7]=3[F:26])=[C:17]([F:18])[N:16]3[N:19]=[CH:20][CH:21]=[C:15]3[N:14]=2)=[N:24][N:25]=1
Reactant: NNC(=O)c1nc2ccnn2c(F)c1Nc1ccc(Br)cc1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2nc3ccnn3c(F)c2Nc2ccc(Br)cc2F)o1
Reaction time: 17 h

Procedure:
Cyanogen bromide (2.02 equivalents) is added to a suspension of 6-(4-bromo-2-fluorophenylamino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid hydrazide (1.00 equivalent) in dioxane followed by an aqueous NaHCO3 solution (1.01 equivalents). After 17 hours, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product is purified by flash chromatography as necessary.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:54]3[CH2:55][CH2:56][CH:51]([O:50][CH3:49])[CH2:52][CH2:53]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methoxy piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][S:9]([C:12]2[C:13](C)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([Br:19])[C:5]([Br:20])=[C:4]([Br:21])[C:3]=1[Br:22].[C:23]1(C)C(S(Cl)(=O)=O)=CC=CC=1>>[Br:1][C:2]1[C:7]([O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[C:6]([Br:19])[C:5]([Br:20])=[C:4]([Br:21])[C:3]=1[Br:22]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccccc1S(=O)(=O)Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)c(Br)c(Br)c(Br)c2Br)cc1

Procedure:
The o-toluenesulfonic acid pentabromophenyl ester can be prepared in the same manner by using the same molar amount of o-toluenesulfonyl chloride instead of the para compound.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH:18]([C:20]1[N:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:43])[CH2:32][N:33]3[C:37]([CH3:38])=[CH:36][C:35]([C:39]([F:42])([F:41])[F:40])=[N:34]3)[CH2:27][CH2:26]2)[S:23][CH:24]=1)=[CH2:19].C(N(CC)CC)C>CN(C)C=O.O>[C:2]1([C:1]2[CH2:19][CH:18]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][N:28]([C:31](=[O:43])[CH2:32][N:33]5[C:37]([CH3:38])=[CH:36][C:35]([C:39]([F:41])([F:40])[F:42])=[N:34]5)[CH2:27][CH2:26]4)[S:23][CH:24]=3)[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: C=Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3CC(c4ccccc4)=NO3)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of benzaldehyde oxime (49 mg, 0.4 mmol) in N,N-dimethylformamide (3 mL) was added N-chlorosuccinimide (54 mg, 0.4 mmol), followed by addition of 4-(4-ethenyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 4, Step C) (103 mg, 0.27 mmol) and triethylamine (41 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for 5 h, then diluted with water, extracted with dichloromethane (2×). The organic layers were combined and dried (MgSO4), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using 55-70% ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20](O)([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 110 °C
Yield: 81.4 %

Procedure:
4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol (2-1; 594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in 13 mL toluene and the stirred mixture was heated to 110° C. for 11 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was washed with additional ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 461 mg of compound 3-1 which was recrystallized from hexane: mp 86.7-88.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:15])=[N:20][CH:21]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (425 mg, 2.05 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 100 mg, 2.05 mmol) in THF (6 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (390 mg, 8.0 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 50% ethyl acetate in heptane) afforded the title compound (621 mg, 88%) as a white solid. MS: m/e=343.3 [M+H]+.
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:28](C(ON1C(=O)CCC1=O)=O)[CH2:29][CH3:30]>>[NH:27]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C@H:28]([C:20]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:22])[CH2:29][CH3:30]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
Using 6.50 g of Boc-Asn-Leu-OEt and 5.48 g of Boc-Abu-OSu, the same procedure as in Reference Example 35 was repeated to obtain 7.20 g (yield: 90.2%) of the above objective compound having a melting point of 152°-155° C.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]#N)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[OH-:16].[Na+].[OH2:18]>>[CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]([OH:18])=[O:16])[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CS(=O)(=O)c1cccc(C#N)n1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Product: CC(C)CS(=O)(=O)c1cccc(C(=O)O)n1
Temperature: 90 °C
Yield: 85 %

Procedure:
A suspension of 6-(isobutylsulfonyl)picolinonitrile (126 mg, 562 μmol) and powdered sodium hydroxide (89.9 mg, 2.25 mmol) in water (15 mL) was heated to 90° C. for 24 h, poured into ice water/0.1 N aqueous HCl solution (1:1) and extracted 3 times with EtOAc. The organic layers were washed with ice water/brine (1:1), dried over Na2SO4 and concentrated in vacuo to give the title compound (116 mg, 85%) as white solid which was sufficiently pure to be used in the next reaction step. MS (EI): m/e=241.9 [M−H]−.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CC#N>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (6.47 g, 31.88 mmol, 1.0 eq.) in 250 ml of MeCN, was added dropwise DBN (4.35 g, 35.07 mmol, 1.0 eq.). The reaction was stirred for 5 mins before addition of 2-bromo-6-(bromomethyl)pyridine (8.8 g, 35.07 mmol, 1.1 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. MeCN was evaporated and the residue was purified by chromatography on silica gel to yield N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (9.4 g, 75% yield, 10:1 mixture of stereoisomers) as a pale yellow oil.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[N:23]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:22]=2)[CH2:17][CH2:16]1.N>ClCCl.O>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[CH:22]=[C:21]2[CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]([NH2:3])=[O:1])[CH2:16][CH2:17]1
Reactant: N#C[O-]
Reactant: NCCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Agent: N
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)NCCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.6 %

Procedure:
Potassium cyanate (4.9 g) is suspended in dichloromethane (50 ml) followed by dropwise addition of trifluoroacetic acid (4.4 ml) at 0° C. A solution of 3-[1-(2-aminoethyl)piperidin-4-yl]-5-chloro-1-(4-fluorophenyl)- 1H-indole (10.8 g) prepared according to Example 1 in dichloromethane (100 ml) is added dropwise followed by stirring for 6 hours at room temperature. Water (100 ml) is added and the reaction mixture is made alkaline with concentrated ammonia. The phases are separated, followed by extraction with dichloromethane. The combined organic phases are dried over magnesium sulfate. Removal of solvent under vacuum gives a heavy oil which is purified by flash chromatography (silica gel, eluent: triethylamine/methanol/ethyl acetate 5:20:75). About 7.9 g of the title compound is isolated as a crystalline material.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([S:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Sc1ccccc1
Product: Clc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2,5 Dichloropyridine (8.9 g, 60 mmol) and thiophenol (6.1 mL, 60 mmol) were heated to 150° C. for 41 h. The mixture then was removed from heat and cooled to room temperature. Column chromatography (silica gel, 200 mL) using hexanes as eluent gave 8.06 g of the title compound; IR (liq.) 1564, 1548, 1476, 1440, 1356, 1122, 1092, 1024, 1006, 821, 748, 727, 706, 691, 628 cm−1. 1H NMR (CDCl3) δ 6.8, 7.4, 7.6, 8.38.