Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[C:9]([C:12](=[O:15])[CH2:13]Br)[CH:10]=2)[C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3]1.[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:7][C:8]=2[CH3:16])=[O:15])[CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(=O)CN1CCC(NC(=O)c3ccccc3)CC1)C(C)(C)CC(C)C2(C)C
Yield: 24.1 %

Procedure:
A mixture of 1,1,3,4,4,6-hexamethyl-7-bromoacetyl-1,2,3,4-tetrahydronaphthalene (7 g.), 4-benzamidopiperidine (4.27 g.) and triethylamine (3.5 g.) was refluxed in 100 ml. EtOH for 2 hours. The resulting yellow solution was cooled, whereupon the product crystallised. This was recrystallised twice from EtOH/water to give the title compound (2.3 g.) as a pale yellow solid, m.p. 153° (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:5]=2[CH2:4][O:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1.CCOC(C)=O>[CH3:16][S:17]([O:14][CH2:13][CH2:12][C:11]1[C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)(=[O:19])=[O:18]
Reactant: CC1(C)OCc2c(CCO)cccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OCc2c(CCOS(C)(=O)=O)cccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (400 mg, 1.92 mmol, 1 eq.) in THF (20 mL) were added MsCl (438 mg, 3.84 mmol, 2.0 eq.) and TEA (0.8 mL, 5.76 mmol, 3.0 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (400 mg, crude) as a pale brown oil, which was used for next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].CC(N(C)C)=O.[C:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:3][N:2]([CH3:1])/[CH:4]=[C:20](/[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)\[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccncc1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
Pyridinium p-toluene sulfonate (7.8 mg; 0.031 mmol) and DMF.DMA (5.35 mL; 40.3 mmol) were added to a solution of ethyl isonicotinoylacetate (6.0 g; 31.0 mmol) in anhydrous toluene (40 mL) and the mixture was heated to 90° C. for 3 hours. The mixture was cooled, water (50 mL) was added and the product was extracted with DCM (3×50 mL). The combined organic fractions were passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a purple oil (7.68 g; 99.8%). The compound was used directly without any further purification.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[C:7]([C:20]#[N:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)[Cl:25]>Cl.C(O)C>[ClH:25].[C:1]([C:5]1[S:9][C:8]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]([NH2:21])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Yield: 90 %

Procedure:
Add 5-tert-butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile (21.2 g, 70 mmol) to a solution of tin(II)chloride dihydrate (46.1 g, 209 mmol) in conc. HCl (200 mL) and ethanol (600 mL). Reflux the mixture for 2 hours. Concentrate the solution to 200 mL and add to water (1 L). Filter and wash with water then hexanes to obtain the title compound as an orange powder (19.4 g): 1H NMR (DMSO-d6) δ 1.27 (s, 9H), 6.86 (d, 1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.11 (t, 1H), 8.69 (s, 1H), 9.11 (s, 1H), 9.52 (s, 1H), 10.88 (s, 1H); MS (APCI) m/z (rel intensity) 272 (100).
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[C:9](Cl)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O.[OH-].[Na+]>C(Cl)Cl>[C:9]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)C(C)N
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (291 mmol) of D,L-alanine methyl ester hydrochloride and 64.77 g (640 mmol) of triethyl)amine are initially charged in 300 ml of dry methylene chloride at 0° C. 43.24 g (291 mmol) of heptanoyl chloride in 50 ml of methylene chloride are added dropwise. The mixture is allowed to warm to RT and stirred at this temperature for 2 h. The precipitate is filtered off and the methylene chloride phase is extracted with saturated sodium bicarbonate solution and wraith saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in 300 ml of methanol. 300 ml of water, in which 46.55 g (1164 mmol) sodium hydroxide are dissolved, are added to this solution, and the mixture is stirred at RT for 2 h. The mixture is filtered, the methanol is evaporated using a rotary evaporator and the aqueous phase that remains is acidified to pH 1–2 using conc. Hcl. The precipitated product is filtered off and dried. Extraction of the aqueous phase with ethyl acetate gives a second product fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Reactant: OB(O)c1ccncc1
Product: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1-c1ccncc1
Yield: 63 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 4-pyridinyl boronic acid instead of phenyl boronic acid to obtain the title compound (32 mg, 63%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[CH:22]=[N:23][C:24]([N+:27]([O-])=O)=[CH:25][CH:26]=4)[CH:17]=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Sn](Cl)Cl>CCOC(C)=O.CCO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[N:23][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2ccc(-c3cc(Oc4ccc([N+](=O)[O-])nc4)ccn3)cc2)CC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCC(c2ccc(-c3cc(Oc4ccc(N)nc4)ccn3)cc2)CC1
Temperature: 65 °C
Yield: 136 %

Procedure:
A solution of 2-(4-(1-methylpiperidin-4-yl)phenyl)-4-((6-nitropyridin-3-yl)oxy)pyridine (0.199 g, 0.510 mmol) in EtOAc (10 mL) and EtOH (10 mL) was treated with tin(II) chloride dehydrate (0.575 g, 2.55 mmol), heated at 65° C. for 4 h, then heated 75° C. overnight. Additional tin(II) chloride dehydrate (300 mg) was added, the mixture heated at 80° C. for 6 h, treated with another portion of tin(II) chloride dehydrate (300 mg) and heated at 80° C. for 3 days. Additional tin(II) chloride dehydrate (300 mg) was added and the mixture heated at 80° C. overnight. The mixture was cooled to RT, concentrated to dryness, treated with EtOAc and satd. NaHCO3, filtered through diatomaceous earth and the filter cake rinsed with EtOAc/THF. The filtrate was treated with solid NaOH (2 g) and NaCl until the aqueous layer was saturated, extracted with 3:1 EtOAc/THF (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (250 mg, >100%). MS (ESI) m/z: 361.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([SiH2:18][O:19][C:20]([CH3:30])([CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=1[NH2:28])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:28][C:22]1[C:21]([C:20]([CH3:30])([CH3:29])[O:19][SiH2:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:27][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][N:9]=1)=[O:13]
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (1.0 g, 4.13 mmol) and 3-(tert-butyl-dimethyl-silanyloxymethyl)-benzene-1,2-diamine Compound 6a (1.05 g, 4.17 mmol), HATU (1.58 g, 4.16 mmol) and DIPEA (2.5 mL, 35.9 mmol) in DMF (50 mL) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), then sequentially washed with hydrochloric acid (20 mL, 1M), water (30 mL×3) and brine (20 mL). The organic solution was evaporated to dryness in vacuo and purified by silica gel chromatography (10% to 50% of ethyl acetate in hexanes) to yield 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid [2-amino-3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-amide Compound 6b (1.21 g, 61% yield) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=2.1 Hz), 8.73 (s, 1H), 8.67 (d, 1H, J=2.1 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.01 (d, 1H, J=7.2 Hz), 6.83 (t, 1H, J=7.2 Hz), 4.78 (s, 2H), 0.95 (s; 9H), 0.11 (s, 6H); MS (ESI) m/z: 477 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ccccn4)cc2)CO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4cccc[n+]4[O-])cc2)CO3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.7 %

Procedure:
To a solution of N-[4-(2-pyridylmethyl)phenyl]-6-(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (250 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3) concentrated to give crystals, which were recrystallized from chloroform-ethanol to give N-[4-(1-oxidopyridin-2-ylmethyl)phenyl]-6-(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (Compound 200) (191 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O-:17])=[O:16])[N:12]=[C:11]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC1C=C(NC(C2C=CC(C)=CC=2F)=N)C=CC=1)C.C(=O)(O)[O-].[Na+].BrCC(=O)C(OCC)=O>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)[O-])nc2-c2ccc(C)cc2F)c1
Agent: CCOC(=O)C(=O)CBr
Agent: CCOc1cccc(NC(=N)c2ccc(C)cc2F)c1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2F)c1
Temperature: 25 °C

Procedure:
Ethel 1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a viscous yellow oil. LC/MS 369.2 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26]CC>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH3:26]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodobutane for 1-iodopropane while making non-critical variations the title compound was obtained as 128 mg (50%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.94 (br s, 1H), 7.37-7.30 (m, 2H), 7.25 (dd, J=8.0 Hz, 0.9 Hz, 1H), 7.17-7.13 (m, 1H), 7.05-7.04 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.95-6.93 (m, 1H), 3.96-3.87 (m, 2H), 3.11-3.00 (m, 2H), 2.96-2.81 (m, 4H), 2.44-2.39 (m, 2H), 1.59-1.51 (m, 2H), 1.27-1.17 (m, 2H), 0.80 (t, J=7.4 Hz, 3H); HRMS (FAB) calcd for C22H26N2O+H1: 335.2123 found 335.2137.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH:29]1[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH2:28]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Product: COc1ccc2cc(OC3CCC4(CCNCC4)CC3)ccc2c1

Procedure:
Was prepared according to method A from 6-methoxy-2-naphthol and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[C:8]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=1
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Product: CCCCCCCCOc1cc(OCCCCCCCC)cc(C(=O)OC)c1

Procedure:
200 ml of ethyl alcohol and then 2.3 g of purified sodium are introduced into a 500 ml Erlenmeyer flask. A reflux condenser is fitted to the Erlenmeyer flask and the reaction medium is stirred with a magnetized bar. When the sodium ethylate is formed, 8.4 g of methyl-3,5-dihydroxybenzoate is added, accompanied by stirring. As soon as the medium has become homogeneous, 20.26 g of distilled octyl bromide are added dropwise. Heating under refluxing takes place for 20 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 50.8 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-2-ylcarbamate (200 mg, 0.739 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (138 mg, 51.1%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH3:32][C:33]1[C:37]([NH2:38])=[C:36]([CH3:39])[NH:35][N:34]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:38][C:37]2[C:33]([CH3:32])=[N:34][NH:35][C:36]=2[CH3:39])=[O:20])[CH:8]=1)=[O:5]
Reactant: Cc1n[nH]c(C)c1N
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1NC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 110 mg, 0.24 mmol), 3,5-dimethyl-1H-pyrazol-4-amine (30 mg, 0.27 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DMF (1.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (101 mg, 0.26 mmol) and the reaction was stirred for 2 hours at room temperature. The reaction was concentrated in vacuo and the residue purified using Preparative HPLC to afford the title compound (65 mg, 49%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]1=[O:27].N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:19]1=[O:27]
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 68.6 %

Procedure:
3-(3-Dimethylaminopropyl)-2-formyl-4,5,6,7-tetrahydro-1H-indole (1.8 g), 1 g of 2-oxindole and 0.1 g of piperidine in 10 mL of ethanol was refluxed for 4 hours and then cooled to room temperature. The precipitate which formed was collected by vacuum filtration and washed with 4 mL of ethanol. The solids were slurry-washed with 8 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 3 mL of ethanol and vacuum dried to give 1.8 g (70% yield) of 3-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]1([CH2:14][CH2:15][N:16]2[C:20]3[N:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:19]=3[CH:18]=[C:17]2[CH2:27][N:28]2[C:32](=[O:33])[C:31]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:30]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:29]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(OC(=O)C)(=O)C>ClCCl.C(N(CC)CC)C>[C:3]([N:36]1[CH2:37][CH2:38][C:31]2([N:30]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:29][N:28]([CH2:27][C:17]3[N:16]([CH2:15][CH2:14][CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:20]4[N:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:19]=4[CH:18]=3)[C:32]2=[O:33])[CH2:34][CH2:35]1)(=[O:4])[CH3:2]
Reactant: N#Cc1ncc2cc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)n(CCC3CCCCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CCC1CCCCC1)CN2c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of 7-(2-cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt (142 mg, 0.28 mol) in dichloromethane (2 ml), triethylamine (395 μl) and acetic anhydride (54 μl, 0.57 mmol) are added at 0° C. The reaction mixture is stirred for over night at room temperature, quenched with ice-water and extracted with ethyl acetate. The combined extracts are washed with H2O, brine and dried over sodium sulphate. Chromatography on silica gel gives 90 mg of 6-(8-acetyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 58% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1.[C:29]([OH:32])(=[O:31])[CH3:30].C(=O)(O)[O-].[Na+].ClC1C=C(C(F)(F)F)C=C(Cl)C=1CC1N(C)C2C(C(CC)C(O)C)=CC=CC=2N=1>O1CCCC1>[C:29]([O:32][CH:16]([CH3:17])[CH:15]([C:11]1[C:8]2[N:9]([CH3:10])[C:5]([CH2:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:20]=3[Cl:28])=[N:6][C:7]=2[CH:14]=[CH:13][CH:12]=1)[CH2:18][CH3:19])(=[O:31])[CH3:30]
Reactant: CC=C(CC)c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12
Reactant: CC(=O)O
Agent: CCC(c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12)C(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12)C(C)OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 25 %

Procedure:
To a solution of 2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-7-[1-ethylprop-1-en-1-yl]-1-methyl-1H-benzimidazole (60 mg, 0.141 mmol) in tetrahydrofuran (1.5 mL) was added a solution of borane-dimethyl sulfide complex in tetrahydrofuran (1.9 M, 1.5 mL, 2.81 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 15 hr, acetic acid (3.0 mL) was added thereto and the mixture was heated at 120° C. for 2 hr. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL, twice). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-50% ethyl acetate/n-hexane gradient mixture to give 2-{2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-1-methyl-1H-benzimidazol-7-yl}-1-methylbutyl acetate (17 mg, 0.0349 mmol, 25%) and 3-{2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-1-methyl-1H-benzimidazol-7-yl}pentan-2-ol (less polar diastereomer; 2.4 mg, 0.00539 mmol, 4%, more polar diastereomer; 2.5 mg, 0.00562 mmol, 4%).