Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([CH:45]=O)=[N:43][CH:44]=1>CO.O>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)[CH2:45][C:42]2[CH:41]=[CH:40][C:39]([CH3:38])=[CH:44][N:43]=2)=[CH:13][CH:12]=1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CNCc2nccn2C)cc1
Reactant: Cc1ccc(C=O)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ccc(C)cn2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
The compound (782 mg) obtained in Example 20-3 was dissolved in anhydrous methanol (12 ml) and then added with sodium cyanoborohydride (380 mg) and acetic acid (1.5 ml). Then, the solution was added with a methanol solution (2.0 ml) containing the compound (289 mg) obtained in Example 20-4 at −10° C. and then stirred at room temperature for 12 hours under a nitrogen atmosphere. After completion of the reaction, water was added thereto to stop the reaction. The solvent was distilled off under reduced pressure and chloroform and a 1 mol/l sodium hydroxide aqueous solution were added to the residue to make the pH of the aqueous layer about 10, followed by extraction of the aqueous layer with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The resultant was then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining a hydrochloride (316 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]([CH:20](OC)[O:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.C(OC(=O)C)(=O)C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)C(c1ccccc1Oc1cc(Cl)ncn1)C(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A mixture of methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate (17.98 g), acetic anhydride (5.16 g) and toluene (73 ml) was stirred at 90° C. for 20 minutes. Methane sulphonic acid (0.49 g) was added to the mixture and the mixture was heated at 90° C. for 1 hour. The mixture was cooled to room temperature, washed with cold water (25 ml) and with hot (50° C.) water (2×25 ml). The organic layer was evaporated at 75° C. (initially on a rotary evaporator, then at circa 15 mm Hg) to leave (E)-methyl 2-[-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as a solid (16.1 g).
Reaction SMILES: C(OC(C1C(C)=NC(N2CCCCC2)=NC=1C1C=CC(C)=CC=1)C(OC)=O)(C)(C)C.[C:31]([O:35][CH:36]([C:41]1[C:42]([C:54]([CH3:57])([CH3:56])[CH3:55])=[N:43][C:44]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[N:45][C:46]=1[CH3:47])[C:37]([O:39]C)=[O:38])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][CH:36]([C:41]1[C:42]([C:54]([CH3:57])([CH3:56])[CH3:55])=[N:43][C:44]([N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)=[N:45][C:46]=1[CH3:47])[C:37]([OH:39])=[O:38])([CH3:33])([CH3:34])[CH3:32]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1C(C)(C)C
Agent: COC(=O)C(OC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Product: Cc1nc(N2CCCCC2)nc(C(C)(C)C)c1C(OC(C)(C)C)C(=O)O

Procedure:
This compound is prepared following the same procedure as described for example 185 wherein methyl 2-tert-butoxy-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate is replaced by methyl 2-tert-butoxy-2-(4-tert-butyl-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)acetate.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])O.[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6])[CH3:23]
Reactant: CCO
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Cl)nc1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To ethanol (20 mL) were added concentrated sulfuric acid (10 mL) and 2-amino-6-chloro-nicotinic acid (6.3 g, 27 mmol, purity: 75%) described in Manufacturing Example 26-1-1 on an ice bath, which was stirred overnight at 65° C. The reaction mixture was gradually cooled, after which a sodium hydrogencarbonate aqueous solution was added to neutralize the mixture. The precipitated solids were filtered to obtain the title compound (4.1 g, 74%).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1C=CC=CC=1>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]=[CH:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3)cc1
Temperature: 50 °C

Procedure:
To a solution of 0.13 g (0.38 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 15 ml of dry benzene was added 0.67 g (2.90 mmol) of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent). The resulting mixture was heated at 50° C. for 30 minutes, cooled to room temperature, partitioned between water (10 ml) and EtOAc (20 ml) and the layers separated. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: [NH:1]([C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19]>>[NH:1]([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Product: CC(=O)OCCn1cnc2c(Cl)nc(Nc3ccccc3)nc21
Yield: 47 %

Procedure:
2-Anilino-6-chloropurine was reacted with 2-acetoxyethyl bromide as described above in A.a. 2-Anilino-6-chloro-9-(2-acetoxyethyl)purine was isolated in a 47% yield, mp 193°-194° C.
Reaction SMILES: [H-].[Na+].C(O)C.[CH:6]1([C:11]([O:13]C)=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>C1COCC1>[CH:6]1([C:11](=[O:13])[CH2:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C1CCCC1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(=O)C2CCCC2)cc1
Yield: 55.8 %

Procedure:
Sodium hydride (1.378 g, 59.9 mmol, 60% suspension in mineral oil) and ethanol (2.0 mL) were added to a solution of methyl cyclopentanecarboxylate (6.14 g, 47.9 mmol) and 1-(4-methoxyphenyl)ethanone (6.00 g, 40.0 mmol) in THF (200 mL). The mixture was heated to reflux for 11 h, quenched with water (100 mL) and acidified to pH˜2 with 1 N HCl. The THF solvent was evaporated in vacuo. The residue was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with hexanes and small amount of toluene and eluting with 0-15% ethyl acetate in hexanes, gave 1-cyclopentyl-3-(4-methoxyphenyl)propane-1,3-dione as yellow liquid (5.494 g, 56% yield). MS (ES+) m/z: 247 (M+H); LC retention time: 4.510 and 3.578 min, likely a mixture of keto and enol forms (analytical HPLC Method A).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.C(=O)([O-])O.O1CCOCC1.O.C(=O)(O)[O-].[Na+]>CO>[NH2:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:16])([CH3:17])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(N)c2cc(C(C)(C)C)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
A methanol (60 ml) solution of methyl 4-acetylamino-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylate (I-253) (2.28 g, 6.24 mmol) and 4 N hydrogen carbonate/1,4-dioxane solution (15.6 ml, 62.4 mmol) were stirred overnight at room temperature, then heated up to 50° C. and stirred for 5 hours. The reaction liquid was put into saturated sodium bicarbonate water (300 ml), followed by extraction with ethyl acetate (200 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→1:1) to obtain the entitled compound (972 mg, 48%) as a yellow white solid. Starting material recovery, 1.10 g (48%).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O.ClCCl>[OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:34]([CH3:35])[CH3:33])=[O:28])=[N:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=C(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 1 h

Procedure:
To a solution of 5-({3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carboxylic acid (Example 18, 0.030 g, 0.070 mmol) in 1 mL of DMF was added dimethylamine (0.087 mL, 0.17 mmol), triethylamine (0.019 mL, 0.14 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.046 g, 0.10 mmol). After 1 h, additional dimethylamine (0.17 mL, 0.35 mmol) was added. After 2 h, the mixture was diluted with water and dichloromethane, and the organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 459.2039 for [M+H]+ [Calc'd for C26H27N4O4, [M+H]+=459.2027]: 1H NMR (400 MHz, CDCl3) δ 8.89-8.87 (m, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.76 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63-7.54 (m, 2H), 7.41 (s, 2H), 4.82-4.75 (m, 1H), 4.34 (br s, 1H), 4.27 (s, 2H), 4.23-4.18 (m, 2H), 4.03 (s, 1H), 3.58-3.51 (m, 1H), 3.34-3.28 (m, 1H), 3.09 (s, 3H), 2.99 (s, 3H), 2.23-2.12 (m, 1H), 2.00-1.91 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][OH:18].C[O-].[Na+].Cl>CO>[CH2:1]([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:17][OH:18])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCOc1ccc(C(=O)OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCOc1ccc(C(=O)NO)cc1
Temperature: 25 °C

Procedure:
Compound HA-3 (4-Butoxybenzohydroxamic Acid) was synthesised from methyl 4-butoxybenzoate. Hydroxylamine hydrochloride (6.95 g, 100 mmol) was dissolved in AR Grade methanol (20 mL) under Argon, then added to NaOMe (25% w/w in MeOH) 52.9 mL, 231 mmol) under Ar with ice cooling. A solution of methyl 4-butoxybenzoate (10.0 g, 48.0 mmol) in MeOH (50 mL) was then added, and the reaction stirred at room temperature under Ar. After 3 weeks, the reaction mixture was acidified to pH 6 with conc. HCl (caution!). The mixture was filtered and the filtrate evaporated to give a precipitate. This was extracted with CHCl3, the combined extracts dried (MgSO4) and the solvent evaporated. The residue was recrystallised from EtOH to give 4-butoxybenzohydroxamic acid as crystals, m.p. 152.6°-152.9° C. (8.25 g, 82%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[N:15]1([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH:19]=[N:18][N:17]=[N:16]1
Reactant: c1ccc(COc2cccc(-n3cnnn3)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(-n2cnnn2)c1
Yield: 88.4 %

Procedure:
To a solution 1-(3-Benzyloxy-phenyl)-1H-tetrazole (0.640 grams, 2.54 mmole) in ethanol (15 ml) was added 10% palladium on carbon (˜0.100 g). This was stirred under hydrogen balloon over night. The catalyst was removed by filtration, and the solution was concentrated to give a white solid (0.364 g). M.P. 171-172° C.; MW 162.12; MS (m/e) 163 (M++1).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Mg].II.C[O:18]B(OC)OC.OO>O1CCCC1.O.C(O)(=O)C>[OH:18][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: COCCOCc1ccc(Br)cc1
Agent: II
Agent: OO
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COCCOCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 139.9 %

Procedure:
2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal of iodine was added and the mixture heated until an exothermic reaction commenced. A solution of the remaining 2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintain the temperature of the reaction mixture at reflux. When the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10° C., dropwise over 45 minutes whilst maintaining the temperature below -5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropwise addition of 30% hydrogen peroxide (11.77 ml) in water (11 ml) whilst maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in ether (100 ml) and extracted into IM aqueous sodium hydroxide (50 ml×3). The aqueous extract was acidified with 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil; NMR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:15][C@@H:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[I:21]N1C(=O)CCC1=O>ClCCl>[I:21][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:12]=1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2cn(C)cn2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2I)cc1
Reaction time: 16 h

Procedure:
To a solution of Ethyl (1S,2S)-2-[4-(1-methyl-1H-imidazol-4-yl)phenyl]cyclopropanecarboxylate (product of Step 1, 2.8 g, 10.36 mmol) in dichloromethane (104 mL) was added N-iodosuccinimide (2.1 g, 9.33 mmol). The reaction mixture was stirred at it for 16 h. The mixture was diluted with dichloromethane and washed with aqueous sodium thiosulfate, followed by three washes with water then dried (MgSO4). The solvent was concentrated to afford the title compound as an orange oil which could be used in the next Step without further purification. LCMS: [M+1]+=396.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[C:11](=[O:24])[C:10](NC3C=CC(OC(F)(F)F)=CC=3)=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:39])C.COC1CCC(OC)O1.C(O)(C(F)(F)F)=O>O.C1COCC1>[OH:39][C:10]1[C:11](=[O:24])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=2)[CH:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: CC(=O)O
Reactant: Cc1cccc(C2C=C(Nc3ccc(OC(F)(F)F)cc3)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Agent: COC1CCC(OC)O1
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C2C=C(O)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Temperature: 40 °C

Procedure:
Charge THF (20 mL, 5 vols) to a flask containing (±)-5-(3-methyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (4.18 g, 8.22 mmol). Add acetic acid (1.88 mL, 32.89 mmol,) to the above clear solution to afford a yellow solution. Add 2,5-dimethoxytetrahydrofuran (1.28 mL, 9.87 mmol,), then add water (0.2 mL, 9.87 mmol). Add TFA (1.25 mL, 16.44 mmol,) to the reaction mixture and observe a slight exotherm (23 to 30° C.). Heat the reaction mixture to 40° C. for 22 hours. Pour the brown solution into water (50 mL) and extract with ethyl acetate (50 mL×2). Wash the organic phase with saturated sodium bicarbonate solution (20 mL×2), brine (50 mL), dry over magnesium sulfate and evaporate to afford the titled compound. MS (m/z): 350.1 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>CO>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: Clc1nncc2ccccc12
Reactant: NN
Solvent: CO
Solvent: O
Product: NNc1nncc2ccccc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A 2 L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser, and was charged 375 mL of hydrazine hydrate; the solution was then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt was added in portions at a rate to maintain the solution temperature at 0 to 5° C. After addition, the solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and 150 mL of methanol was added, the solution stirred for 3 hrs, and the resulting solid material was filtered, washed with 150 mL of cold methanol, and dried under vacuum at 35° C. Yield 99%.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]=[O:10]>CCOCC>[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]([OH:10])[CH3:5]
Reactant: CI
Reactant: CC1=CCCC(C)(C)C1C=CC(C)C=O
Agent: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Product: CC1=CCCC(C)(C)C1C=CC(C)C(C)O
Temperature: 30 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A solution of methylmagnesium iodide, prepared from 11 g of magnesium shavings and 76 g of methyl iodide, in 700 ml of absolute ether is added dropwise at -10° C under nitrogen to a solution of 62 g of 2-methyl-4-(2,6,6-trimethyl-2-cyclohexenyl)-3-butenal in 700 ml of ether. The mixture is stirred for 4 hours at 30° C and then poured on to an excess of ice-cold ammonium chloride solution. The mixture is extracted with ether in the usual manner, the extract is washed neutral with water and dried over anhydrous sodium sulphate to give, after removal of the solvent, 66 g of a yellow, slightly viscous oil which, after distillation in vacuo, yields 52 g of 3-methyl-5-(2,6,6-trimethyl-2-cyclohexenyl)-4-penten-2-ol; b.p.0.008 = 90°; nD20 = 1.4890. This alcohol has a very fine, tenacious sandalwood odour.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:25](=[O:26])[CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)Cc1cccs1
Product: Cc1nc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[N+](C)([O-])=O>[CH:6]([C:5]([C:14]1[CH:15]=[CH:16][C:11]([CH3:17])=[CH:12][CH:13]=1)=[O:9])([CH3:8])[CH3:7]
Reactant: Cc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C(=O)C(C)C)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
At 10° C. a solution of 75 g AlCl3 in 100 ml nitromethane is added to a mixture of 49 g isobutyroyl chloride, 50 ml nitromethane and 100 ml toluene, after which the mixture is stirred during one hour. Then the reaction mixture is poured out into ice and extracted with ether. The ether solution is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain p-tolyl isopropyl ketone in a yield of 90%. 11 g of this ketone, dissolved in 50 ml methanol, is added to a solution of 10 g NaBH4 in 100 ml methanol/water 1:1. The reaction mixture is stirred during one hour, after that poured out into water and extracted with ether. The solution in ether is dried on MgSO4 and evaporated. Raw 2-methyl-1-(p-tolyl)propanol-1 is obtained in a yield of 97%.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C@@H:3]([CH3:20])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:21])[C@@H:3]([CH3:20])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@H](C)N(C)C)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)N(C(=O)[C@H](C)N(C)C)CC2
Yield: 75.9 %

Procedure:
To a solution of (2S)-N,N-dimethyl-1-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-1-oxo-2-propanamine (2.2 g, 7.50 mmol) in Ethyl acetate (250 mL) was added Pd/C (0.798 g, 0.750 mmol) and the reaction was maintained under 50 psi of H2(g) overnight on the Fisher-Porter apparatus. The reaction was filtered through a celite pad which was washed with ethyl acetate, concentrated by rotary evaporation, and high maintained under vacuum for 12 hours to afford 1-[(2S)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (1.5 g, 76%). ESIMS (M+H)+=264.