Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N1(CCOC2C=CC(CN)=CC=2)CCCCC1.FC(F)(F)S(O[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][CH:54]1[CH2:63][CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:64][CH3:65])[CH:60]=2)[CH2:55]1)(=O)=O>>[CH3:65][O:64][C:59]1[CH:60]=[C:61]2[C:56](=[CH:57][CH:58]=1)[CH2:55][CH:54]([CH2:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[NH:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:17][CH:16]=1)[CH2:63][CH2:62]2
Reactant: COc1ccc2c(c1)CCC(Cc1ccccc1OS(=O)(=O)C(F)(F)F)C2
Reactant: N#Cc1ccc(OCCN2CCCCC2)cc1
Agent: NCc1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Product: COc1ccc2c(c1)CCC(Cc1ccccc1NCc1ccc(OCCN3CCCCC3)cc1)C2

Procedure:
Obtained by reducing 4-(2-piperidin-1-ylethoxy)benzonitrile with lithium aluminum hydride, 4-(2-piperidin-1-ylethoxy)benzylamine (1.3 g) and 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl trifluoromethanesulfonate (1.4 g) were used according to an analogous synthetic method to Example 116 to provide [2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl][4-(2-piperidin-1-ylethoxy)benzyl]amine (1.2 g). A portion thereof (200 mg) was used according to an analogous synthetic method to Example 364 to provide the title compound (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:30][O:31][C:32](=[O:69])[NH:33][CH:34]([C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][CH:47]=[C:48]([C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[C:55](B4OC(C)(C)C(C)(C)O4)[CH:56]=3)[CH:51]=2)[N:49]=1)=[O:39])[CH:35]([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:29])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:55]3[CH:54]=[CH:53][C:52]4[C:57](=[CH:58][CH:59]=[C:50]([C:48]5[N:49]=[C:45]([CH:41]6[CH2:42][CH2:43][CH2:44][N:40]6[C:38](=[O:39])[CH:34]([NH:33][C:32]([O:31][CH3:30])=[O:69])[CH:35]([CH3:37])[CH3:36])[NH:46][CH:47]=5)[CH:51]=4)[CH:56]=3)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CC(=O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(=O)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 120 °C
Yield: 5 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (46.0 mg, 0.1 mmol), [2-Methyl-1-(2-{4-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (54 mg, 0.1 mmol), and Pd[PPh3]4 (11.5 mg, 0.01 mmol) were dissolved in DME (2 mL) under an atmosphere of argon. Saturated, aqueous sodium bicarbonate solution (0.3 mL) was added and the reaction was heated under microwave conditions at 120° C. for 20 minutes. The solids were discarded and the volatiles were removed in vacuo. The crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (4.0 mg) as a TFA salt.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cu][C:15]#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:15]#[N:16])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 160 °C
Yield: 20.3 %

Procedure:
3-iodo-5-nitro-1H-indazole (6.9 g, 23.87 mmol) was taken up in NMP (90 mL) and copper (I) cyanide (4.28 g, 47.7 mmol) was added. The reaction was heated at 160° C. for 1 h, and then cooled to room temperature. The reaction mixture was diluted with EtOAc and filtered through celite, rinsing with EtOAc. The filtrate was washed 2× with water and 2× with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0%-50% EtOAc/Hex. 0.91 g of 5-nitro-1H-indazole-3-carbonitrile was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd].C1(C)C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC(C)=CC=2)=CC=1>[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Pd]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 82.6 %

Procedure:
The title compound was prepared from 4-[3-(3,4-dichlorophenyl)propyl]-phenylamine (600 mg, 2.14 mmol), 2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), cesium carbonate (812 mg, 2.49 mmol), tris(dibenzylideneacetone-dipaladium(0) (49 mg, 0.053 mmol) and (S)-2,2′-bis(di-p-tolylphosphino-1,1′-binaphthyl (98%, (S)-tol-BINAP) (54 mg, 0.080 mmol) (Ligand/Pd=1.5) in anhydrous toluene (15 mL) using the procedure described in Example 2, Step C. This procedure yielded an yellow oil, 0.61 g (1.47 mmol, 69%) of the desired product.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: Clc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)c1cccc(Cl)c1

Procedure:
1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-chloro-3-bromobenzene as the dihalo compound of formula (III).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:7][C:6]=1[O:19][CH3:20])[CH3:4].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH2:3]([C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:13]2[CH2:17][N:16]([CH3:21])[C:15](=[O:18])[CH2:14]2)=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4]
Reactant: CI
Reactant: CCc1c(OC)cc(C2CNC(=O)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C2CC(=O)N(C)C2)cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3.12 g (78 mmol) of a sodium hydride dispersion (60% in oil) were added using a spatula and while stirring to a suspension of 8.85 g (35.5 mmol) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-pyrrolidin-2-one in 250 ml of tetrahydrofuran and 2 ml of dimethylformamide and the mixture was stirred at room temperature for a further hour. Thereafter, the reaction mixture was treated with 3.52 ml (106.5 mmol) of methyl iodide and left to stir at room temperature for a further 16 hours. Subsequently, the reaction mixture was poured on to 400 ml of ice-water and extracted twice with 600 ml of ethyl acetate each time. The combined organic phases were washed twice with 300 ml of saturated sodium chloride solution each time, dried (MgSO4) and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (methylene chloride/methanol 39:1). 8.08 g (86%) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-one were obtained as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2cc(C)no2)cc1
Yield: 81 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206 using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 2-methoxybenzeneboronic acid resulting in an 81% yield of the final product.
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=S)[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](OCC)(=[O:28])[NH:26][NH2:27]>>[N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[C:25](=[O:28])[NH:26][N:27]=[C:12]3[C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)NN
Reactant: O=C(CN1CCCC1)N1c2ccccc2NC(=S)c2cccnc21
Product: O=C(CN1CCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-(pyrrolidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14]C(=O)C)[C:3]([OH:5])=[O:4].Cl>O>[OH:1][C@H:2]([C@H:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3]([OH:5])=[O:4]
Reactant: COc1ccc([C@H](Sc2ccccc2NC(C)=O)[C@@H](O)C(=O)O)cc1
Agent: Cl
Solvent: O
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)O)cc1
Temperature: 15 °C
Yield: 6.8 %

Procedure:
60 g (1.65 mol) of (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-acetylaminophenylthio)propionic acid were suspended in 300 ml of water containing 50 ml of 32% (w/w) hydrochloric acid in the presence of 0.5 g of KI. The mixture was heated to slow reflux for about 3 hours, filtered at about 80° C., separating approximatively 10 g of unsolubles, and the filtered waters were neutralized to pH 6 with 30% (w/w) NaOH, cooled to about 15° C., filtered and thoroughly washed with water. 36 g of (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid were obtained with 80% optical purity 98-100%. The acid pH hot filtered unsolubles consisted of a mixture of non unhydrolyzed compound and of compound cyclized to benzothiazepine ring.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([NH:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])[CH3:16]>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:18][C:15](=[O:17])[CH3:16])[CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
A 1.5 g (7.46 mmol) sample of (S)-1-BOC-2-pyrrolidinemethanol (from Aldrich) and 1.69 g (11.19 mmol) of 3-acetamidophenol (Aldrich) were added to a complex of TPP and TBAD, (prepared as in Example 5b above, 11.19 mmol of each) in 50 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with 100:3 chloroform:methanol to give 1.62 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(O)C>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(-c3ccccc3F)nc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloro-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 16> (100 mg), 2-fluorophenylboronic acid (74 mg), potassium carbonate (145 mg), toluene (3 ml) and ethanol (1 ml) was added bis(tri-tert-butylphosphine)palladium (9 mg) under nitrogen atmosphere and the mixture was stirred at 130° C. under microwave irradiation for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10) to give the title compound 58 mg.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCc1ccccc1
Solvent: ClCCl
Product: O=CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-phenylheptan-1-ol (5 g) in CH2Cl2 (25 mL) was added to a suspension of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane) in CH2Cl2 (25 mL) dropwise with ice-bath cooling. The cooling bath was removed after addition was complete and the resulting mixture was stirred at room temperature for 3 h. After addition of a solution of Na2S2O3 (44 g) in saturated NaHCO3, (35 mL), the resulting mixture was stirred for 45 min and the layers were separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic phases were washed with water, dried over Na2SO4 and concentrated to yield 7-phenylheptanal as an oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To chlorosulfonic acid (248 mL, 3.37 mol) cooled to −3° C. was added dropwise a solution of phenol (70 g, 0.744 mot) in 250 mL of anhydrous methylene chloride over a period of 1 hour under argon gas. The mixture was warmed to rt over 1 h and was stirred at rt for 1.5 h. The mixture was poured over ice, stirred for 30 min, and was extracted with methylene chloride (4×2 L). The resulting organic layer was dried over MgSO4 and concentrated in vacuo to yield 4-hydroxybenzenesulfonyl chloride as a sticky brown solid (41.49 g, 29%): 1H NMR (400 MHz, d6-DMSO) δ 7.29–7.38 (d, 2 H), 6.58–6.69 (d, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[CH:17](O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[CH:7]=[C:8]2[N:9]=[CH:17]1
Reactant: O=CO
Reactant: CNc1ncc(C(F)(F)C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1cnc2cc(C(F)(F)C(F)(F)F)cnc21

Procedure:
A mixture of 0.42 g of N2-methyl-5-pentafluoroethylpyridine-2,3-diamine, 4 ml of formic acid and 0.5 ml of water was stirred under heating and refluxing for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 7.80 g of 3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: CC1(C)C2C(=CC(N[C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:15]=[CH:14][N:13]=3)=CC=2)N(C(=O)C)C1.CC1(C)C2C(=CC([N+]([O-])=O)=CC=2)NC1C(=O)C.O.O.[Sn](Cl)[Cl:52].Cl>C(OCC)C>[Cl:52][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:15]=[CH:14][N:13]=1
Reactant: Cl[Sn]Cl
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc21
Agent: CC(=O)C1Nc2cc([N+](=O)[O-])ccc2C1(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-{3,3-Dimethyl-6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2,3-dihydroindol-1-yl}ethanone. To a solution of 1-(3,3-dimethyl-6-nitro-2,3-dihydroindol-yl)ethanone (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round-bottomed flask at 0° C., was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and concd HCl (0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 5(b), the crude product and 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (0.19 g, 0.75 mmol) provided, after purification by silica gel chromatography (3:2 hexanes/EtOAc), the title product. MS (ESI, pos. ion) m/z: 427 (M+1). MP: 227-230° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)[C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
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: ClCCl
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.66 g, 2.55 mmol), 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid (0.5 g, 2.318 mmol), diisopropylethylamine (0.7 mL, 6.954 mmol) and HATU (0.881 g, 2.318 mmol) in DCM was stirred at rt for 1 h. The reaction mixture was diluted with DCM and washed with satd. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 457 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([O:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([O:29][CH2:30][CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[CH3:28]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CCOCCO
Product: CCOCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 2-ethoxyethanol (76 μl; 0.781 mmol), example 51 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[Na+].Cl.[C:9]([NH2:14])(=[NH:13])[CH2:10][CH2:11][CH3:12].C(Cl)Cl>O>[CH3:5][O:4][C:2]([NH:14][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[O:3]
Reactant: CCCC(=N)N
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCC(=N)NC(=O)OC
Yield: 95 %

Procedure:
222 parts of methyl chloroformate and 337 parts of 50% strength sodium hydroxide solution are added via two inlets to a mixture of 286 parts of butyramidine hydrochloride in 1,300 parts of methylene chloride and 500 parts of water, at from 10° to 15° C., in the course of 25 minutes, while stirring. The mixture is stirred at room temperature for 2 hours, and the organic phase is separated off and concentrated on a rotary evaporator to give 320 parts (95% of theory) of N-methoxycarbonylbutyramidine of nD25 1.4763.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyethylamine (0.343 mL, 3.99 mmol) in DMF (20.0 mL) at room temperature was added potassium carbonate (0.964 mL, 15.98 mmol) followed by 4-nitrobenzyl bromide (1.812 g, 8.39 mmol). The reaction was stirred for 2 hours then quenched with water, extracted with EtOAc and concentrated. The residue was purified by chromatography (20% to 40% EtOAc-hexane) to provide the title compound. MS (DCI) m/z 346 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)Cl>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Br:26])[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CC(=O)OCC(COC(C)=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of acetic acid 3-acetoxy-2-(4-amino-phenyl)-propyl ester (Tetrahedron, 46(20), 7081, (1990), 1.2 g, 5.0 mmol) in DCM (50 mL), NBS (903 mg, 5.07 mol) was added at 0° C. The resulting mixture was stirred at RT for 2 h and subjected to the usual work up to obtain acetic acid 3-acetoxy-2-(4-amino-3-bromo-phenyl)-propyl ester (1.4 g, 89%) which was directly used in the next step.