Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:35].[NH4+].[OH-]>C(O)(=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:26]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1)(=[O:35])[NH2:2]
Reactant: N#Cc1ccc(NC(=O)c2n[nH]c3ccc(-c4cncc(CN5CCCCC5)c4)cc23)cn1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NC(=O)c2n[nH]c3ccc(-c4cncc(CN5CCCCC5)c4)cc23)cn1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of N-(6-cyanopyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (62) (200 mg, 0.45 mmol) in glacial acetic acid (2 mL) heated at 85° C. was carefully added dropwise sulfuric acid (2 mL). The reaction was heated at 85° C. for another 20 minutes before pouring into ice. The solution was basified with cold 5N NH4OH. The solids formed were filtered, washed with cold washed and dried under vacuum. The dry solid was suspended in DCM and a few drops of MeOH were added. The insoluble solids were filtered and discarded. The filtrate was concentrated and suspended again in DCM, boiled for 15 minutes and filtered. The solid was dried under vacuum to give N-(6-carbamoylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (180) as a white solid (192 mg, 0.42 mmol, 93.7% yield). 1H NMR (DMSO-d6) δ ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.49 (s, 1H), 7.65 (d, J=9 Hz, 1H), 7.80 (d, J=9 Hz, 1H), 7.97 (s, 1H), 8.03 (s, 2H), 8.41 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.54 (dd, J=9 Hz, J=2.5 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.15 (d, J=2 Hz, 1H), 10.83 (brs, 1H); ESIMS found for C25H25N7O2 m/z 456.4 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:9]([C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:22])=[C:19]([NH2:20])[NH:21][C:19]=1[NH2:20])=[O:22])[CH3:15]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)c1cccc(C=O)c1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc(C(=O)OCC)c1
Yield: 32 %

Procedure:
Upon boiling a solution of 8.9 g 3-carbethoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 100 ml ethanol for 2 hours, 2,6-diamino-4-(3-carbethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191°C (ethanol) is obtained. Yield: 32% of theory.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]3[C:22]([NH:27][CH2:32][C:31]([OH:35])=[O:34])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH2:28][C@@H:7]([NH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:29])[CH2:8][C:9]=3[C:17]=2[CH:16]=1)#[N:19]
Reactant: O=CC(=O)O
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3NCC(=O)O)c3ccc(C#N)cc23)C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
Dissolve [(S)-4-(2-amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (253 mg, 0.650 mmol) in EtOH (25 mL). Add 3 Å molecular sieves and glyoxylic acid monohydrate (239 mg, 2.60 mmol), then stir at 40-110° C. for 18 h under hydrogen (60 psi, 4.08 bar). Filter the reaction through a pad of diatomaceous earth and wash the catalyst/sieves with THF (50 mL). Combine the filtrate and concentrate in vacuo to a yellow oil. Triturate with water (30 mL) and sonicate the resulting aqueous slurry for 5 min. Filter off a tan solid and dry in vacuo. Triturate the solid with Et2O (5 mL) and sonicate the slurry for 30 min. Filter to obtain 190 mg (65%) of the product as a tan solid. LCMS 100% @ 3.99 min m/z 448 (M+H), 446 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[I:12]Cl.O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]([CH3:8])=[CH:6][C:7]=1[I:12]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Yield: 25.6 %

Procedure:
A solution of 4-amino-3-nitrotoluene (30.4 g) in acetic acid (250 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulfite and after column chromatography yielded 4-amino-3-iodo-5-nitrotoluene (14.2 g). δ (360 MHz, DMSO-d6) 2.19 (3H, s, CH3), 6.88 (2H, bs, NH2), 7.88 (1H, d, 2-H) and 7.94 (1H, d, 6-H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[C:21]([O:23]CC)=O)=[O:14])=[CH:4][CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:21](=[O:23])[CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][N:15]3[C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)Nc1ccc(Cl)c2c1CC(C)O2
Agent: Cl
Solvent: CCO
Product: CC1Cc2c(N3C(=O)C4CCCCN4C3=O)ccc(Cl)c2O1

Procedure:
A mixture of 2.0 g of 34B, 25 mL of ethanol and 25 mL of 2N hydrochloric acid was stirred and refluxed for 2 hours. Then the solvent was evaporated, the residue was mixed with 50 mL of water, and the resulting mixture was extracted with methylene, chloride. The extract was dried (MgSO4) and the solvent was evaporated. The residue was purified by filtration through a short pad of silica gel, with a 1:1 v:v mixture ethyl acetate and hexane as eluent, to give the title compound, as a solid, m.p.: 145°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([O:37][CH3:38])=[C:21]([CH:36]=1)[CH2:22][O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:26][C:25]=1[CH3:35])=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CCO>[CH3:38][O:37][C:20]1[CH:19]=[CH:18][C:17]([CH:15]2[N:6]([CH2:7][CH2:8][O:9][CH3:10])[C:4](=[O:5])[C:3]3[C:2](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:1]2)=[CH:36][C:21]=1[CH2:22][O:23][C:24]1[C:25]([CH3:35])=[CH:26][C:27]([NH:31][C:32](=[O:34])[CH3:33])=[CH:28][C:29]=1[CH3:30]
Reactant: COc1ccc(C=O)cc1COc1c(C)cc(NC(C)=O)cc1C
Reactant: COCCNC(=O)c1ccccc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COCCN1C(=O)c2ccccc2NC1c1ccc(OC)c(COc2c(C)cc(NC(C)=O)cc2C)c1
Yield: 50.8 %

Procedure:
2-amino-N-(2-methoxyethyl)benzamide (71.2 mg, 0.367 mmol), N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (100 mg, 0.305 mmol) and 0.2 equiv of Yb(OTf)3 in 5 mL of EtOH were heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 10-80% ethyl acetate in DCM to give the N-(4-(2-methoxy-5-(3-(2-methoxyethyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzyloxy)-3,5-dimethylphenyl)acetamide (77.9 mg, 0.155 mmol, 50.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (s, 3 H), 2.09 (s, 6 H), 2.90 (ddd, J=13.5, 6.7, 6.5 Hz, 1 H), 3.19 (s, 3 H), 3.31-3.53 (m, 2 H), 3.74 (s, 3 H), 3.86-4.06 (m, 1 H), 4.63 (s, 2 H), 5.85 (d, J=2.3 Hz, 1 H), 6.53-6.69 (m, 2 H), 6.98 (d, J=8.6 Hz, 1 H), 7.12-7.22 (m, 3 H), 7.22-7.31 (m, 2 H), 7.47 (d, J=2.3 Hz, 1 H), 7.61 (d, J=6.7 Hz, 1 H), 9.67 (s, 1 H); LC/MS (electrospray+ve), m/z 504.2 (MH)+, Retention time t=5.27 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C29H33N3O5 [M+H]+504.2496, found 504.2498.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:13][OH:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2cc(F)ccc21
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 5-fluoroindanone (10 g), hydroxylamine hydrochloride (9 g), potassium carbonate (23 g) and water (3.5 ml) in 96% ethanol (40 ml) was heated to reflux, cooled to ca 45 and additional hydroxylamine hydrochloride (4.5 g) and potassium carbonate (11.5 g) were added and refluxed for an additional 30 min. At this time the mixture was poured into cold water (300 ml) and stirred in an ice bath for one hour; 5-fluoroindanone oxime (9.8 g) was isolated by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(N)ccc1-2
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(N)c1Br

Procedure:
1.5 g (4.2 mmol) of t-butyl (S)-7-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 0.783 g (4.4 mmol) of N-bromosuccinimide in 15 ml of dimethylformamide are stirred at room temperature for 45 minutes, subsequently poured into 250 ml of water and extracted three times with chloroform. The chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel using chloroform containing 4% methanol for the elution. Recrystallization of the material obtained from ethyl acetate yields t-butyl (S)-7-amino-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 245°-246°.
Reaction SMILES: C(N(CC)CC)C.C(O[C:11](=[O:14])[CH:12]=[CH2:13])C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][C:17]=1[CH3:24].[H-].[Na+]>CCO>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:11](=[O:14])[CH2:12][CH2:13][NH:23]2)=[CH:18][C:17]=1[CH3:24]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(NN)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N2NCCC2=O)ccc1Br
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Triethylamine (625 μL, 13.1 mmol) and acrylic acid ethyl ester (1.82 mL, 5.74 mmol) were added to a solution of (4-bromo-3-methyl-phenyl)-hydrazine (1.05 g, 5.22 mmol) in EtOH (26.1 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred at 80° C. for 18 hours. The reaction solution was cooled, and 50% NaH (501 mg, 10.4 mmol) was then added to the reaction solution at 0° C. The mixture was stirred at 0° C. for 30 minutes, and 50% NaH (251 mg, 5.20 mmol) was then further added, followed by further stirring for 30 minutes. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate three times. The organic layers were combined and washed with a mixed solution of water:saturated brine (1:1). After separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3-methyl-phenyl)-pyrazolidin-3-one as a brown form (684 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Temperature: 25 °C
Yield: 104.9 %

Procedure:
N-(4-methyl-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (34 g, 0.11 mol) and stannous chloride dihydrate (124.5 g, 0.55 mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (300 ml, 10/1, v/v) and reacted under reflux for 26 hours. The reaction mixture was cooled to room temperature, washed with 10% aqueous hydrochloric acid solution, concentrated, and subjected to column chromatography (chloroform/methanol=9/1, v/v) to give N-(3-amino-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (32 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][CH:47]1[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH:47]3[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(C2CCC(O)CC2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 48.2 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 4-aminocyclohexanol (3.61 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (5.20 g, 48%) as white crystals. The similar reaction as described in Reference Example 18 by using the compound (500 mg, 0.72 mmol) gave the title compound (180 mg, 41%) as white crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:23][Si:22]([C:26]#[C:27][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 3-iodobenzoate (I15) (4.02 g, 13.2 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol) and copper(I) iodide (0.13 g, 0.68 mmol) was dissolved in anhydrous THF (50 mL) under a nitrogen atmosphere and the resulting solution degassed by bubbling nitrogen through it. Triethylamine (9.2 mL, 66 mmol) was added and the mixture was then stirred for 10 minutes before addition of TMS-acetylene (3.8 mL, 27 mmol). The resulting mixture was then stirred for 18 hours. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I16) (3.57 g, 99%) as a cream crystalline solid; 1H NMR (400 MHz, CDCl3) δ 8.06 (ddd, J=1.7, 1.7, 0.5 Hz, 1H), 7.92 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.60 (ddd, J=7.7, 1.4, 1.4 Hz, 1H), 7.35 (ddd, J=7.8, 7.8, 0.5 Hz, 1H), 1.59 (s, 9H), 0.26 (s, 9H). LCMS Method C: rt 7.46 min.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (3.4590 g, 19.09 mmol), 4-aminophenol (3.12 g, 28.6 mmol), and cesium carbonate (18.66 g, 57.3 mmol) in DMSO (63.6 mL) at 110° C. to stir overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 271.1 (M+1).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH:3]([C:12]1[N:17]=[N:16][C:15]([S:18][C:19]2[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=2[CH2:21][NH:22][C:23](=[O:37])[C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:27]=[C:26]([F:36])[CH:25]=2)=[CH:14][CH:13]=1)[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11].[CH3:43]N(C(OC)OC)C>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:11])[C:4]=1[C:3]1[C:2](=[O:42])[N:1]=[CH:43][N:17]2[C:12]=1[CH:13]=[CH:14][C:15]([S:18][C:19]1[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=1[CH2:21][NH:22][C:23](=[O:37])[C:24]1[CH:29]=[C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH:27]=[C:26]([F:36])[CH:25]=1)=[N:16]2
Reactant: COC(OC)N(C)C
Reactant: NC(=O)C(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1Sc1ccc2c(-c3c(Cl)cccc3Cl)c(=O)ncn2n1)c1cc(F)cc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A solution of N-[2-({6-[2-amino-1-(2,6-dichlorophenyl)-2-oxoethyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamide (91 mg, 0.145 mmol) in toluene (4 mL) under an argon atmosphere was treated with DMF-DMA (0.042 mL, 0.315 mmol). The mixture was heated at 100° C. for 1.75 h, then cooled to RT and the precipitate separated by filtration to afford the title compound (77 mg, 84%) as a yellow powder. LCMS (Method 3): Rt 9.8 min, m/z 636 [MH+]. 1H NMR (400 MHz, DMSO-d6): 9.01 (1H, t, J 5.7), 8.82 (1H, d, J 0.7), 7.70 (1H, dd, J 7.7, 1.2), 7.60 (2H, m), 7.58-7.52 (2H, m), 7.49 (1H, dd, J 8.9, 7.3), 7.42 (1H, td, J 7.3, 2), 7.23 (1H, br t, J 1.6), 7.04-6.98 (2H, m), 6.93-6.86 (2H, m), 4.66 (2H, d, J 5.6), 3.73 (4H, t, J 4.7), 3.17 (4H, t, J 4.7).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 183.2 %

Procedure:
While under a nitrogen atmosphere, a solution of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid, methoxy-methyl amide (1.8 g, 6.39 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 31.95 mL, 15.98 mmol) dropwise. After stirring for 1 hour at 0° C. the reaction mixture was warmed to room temperature overnight, poured into water, acidified to pH 3-4 with 1 N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate in heptane) gave 1-[4-(4-chlorophenyl)-cyclohexyl]pent-4-en-1-one as a colorless oil (1.62 g, 92%); 1H NMR (CDCl3, 300 MHz) δ 7.26 (m, 2H), 7.12 (d, J=8 Hz, 2H), 5.81 (m, 1H), 5.02 (m, 2H), 2.58 (t, J=7 Hz, 2H), 2.44 (m, 2H), 2.34 (m, 2H), 1.99 (m, 4H) and 1.47 (m, 4H).
Reaction SMILES: O1CCCC1.[O:6]([C:13]([C:15]1[C:23]2[N:22]=[N:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(OC(Cl)(Cl)Cl)[O:25][C:26]([Cl:29])(Cl)Cl>C(OCC)(=O)C>[C:26]([Cl:29])(=[O:25])[NH2:20].[O:6]([C:13]([C:15]1[C:23]2[N:22]=[N:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C(Oc1ccccc1)c1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)Cl
Reaction time: 1 h

Procedure:
A tetrahydrofuran (75 mL) solution of phenoxycarbonylbenzotriazole (19.1 g) was dropped into an ethyl acetate solution (100 mL) of bis(trichloromethyl) carbonate (9.5 g) at 10° C. The resultant solution was stirred at 40° C. for 3 hrs. After the solvent was distilled away at reduced pressure, 200 mL of hexane were added to the concentrated residue, and the material was stirred for 1 hr. The crystals were filtered out and dried to obtain carbamoyl chloride of phenoxycarbonylbenzotriazole (to be abbreviated as PBT-COCl hereinafter) (22.4 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25]>C(#N)C.CCOCC.[Cu]I>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#CCCCCOCCCCCCBr
Agent: [Cu]I
Solvent: CCOCC
Solvent: CC#N
Product: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
A mixture of 2-bromoquinoline (3.00 g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77 g), BTPC (90 mg), copper (I) iodide (11 mg) and dicyclohexyamine (2.79 g) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with ether (90 ml), filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane:ether (4:1→2:1) gave the title compound as a brown oil (4.25 g), t.l.c. (hexane:ether 2:1) Rf 0.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])(=O)=O)=CC=1>CCO.O>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Solvent: O
Solvent: CCO
Product: CCCC(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
To a stirred solution of aniline 12 (1.0 g, 6.1 mmol) in EtOH:H2O (9:1) was added 2-propylpentyl 4-methylbenzenesulfonate (0.87 g, 3.08 mmol). The reaction mixture was heated under reflux for 4 days, concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc three times. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by flash chromatography (25% EtOAc—hexanes) gave 3-hydroxy-3-(3-(2-propylpentylamino)phenyl)propanenitrile as a colorless semi-solid. Yield (0.3 g, 18%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.0, 8.0 Hz, 1H), 4.95 (dt, J=3.2, 6.0 Hz, 1H), 3.72 (bs, 1H), 3.02 (d, J=6.0 Hz, 2H), 2.80 (d, J=6.8 Hz, 2H), 2.89 (d, J=3.2 Hz, 1H), 1.64-1.57 (m, 1H), 1.37-1.20 (m, 8H), 0.84 (t, J=6.8 Hz, 6H).