Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:26][CH2:25][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:14])([F:15])[F:16])[CH2:11][N:12]=2)=[CH:7][C:2]=1[Br:1])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of {2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl}methanol (0.95 g) and triethylamine (0.41 g) in dichloromethane was added methanesulfonyl chloride (0.35 g) gradually, and the mixture was stirred for 2 hours at room temperature. The reaction liquor was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-benzyl methanesulfonate (1.0 g).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].Cl.[C:7]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:23])=[CH:11][CH:10]=1)#[N:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15](=[O:32])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:31])[C@@H:22]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:23][S:2]([OH:5])(=[O:4])=[O:3])=[CH:33][CH:34]=1)#[N:8]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](N)Cc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](Cc2ccccc2)NS(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
0.58 g (0.33 ml, 5 mmol) of chlorosulfonic acid in 10 ml of DCM was slowly added dropwise at 20° C. with cooling to a solution of 1.8 g (4.36 mmol) of D-phenylalanylproline (p-cyanobenzyl)amide hydrochloride and 1.68 g (13.0 mmol) of diisopropylethylamine in 20 ml of DCM. After stirring at room temperature for 30 min, the mixture was diluted to 100 ml with DCM and extracted initially with 2M HCl and then twice with 10 ml of water, and the organic phase was dried over magnesium sulfate and evaporated in a rotary evaporator. 2.0 g of N-hydroxysulfonyl-D-phenylalanylproline (p-cyanobenzyl)amide were obtained as crude product which was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)cc2F)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a well stirred solution of (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl) pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N-dimethylamino)pyridine (1.69 g, 13.80 mmol) in CH2Cl2 (200 mL) was added solid 4-nitrophenyl chloroformate (2.78 g, 13.80 mmol) at room temperature. The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2×50 mL). The organic layer was separated and dried (Na2SO4). The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20%-50%) as the eluent to give (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (5.37 g, 92%) as a viscous oil.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(F)cc1C(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1ccc(F)cc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoate (1.19 g, 2.64 mmol) obtained from Example 8-(1) was reacted with anisole (1.5 g, 13.9 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.68 g, 13.2 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoyl chloride as a crude product.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[N:7]2.Br[CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:3])=[CH:13][CH:12]=2)[N:7]=[CH:8][C:9]1=[O:14]
Reactant: O=c1cnc2cc(F)ccc2[nH]1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnc2cc(F)ccc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Lithium hydride (57 mg, 7.3 mmol) was added to a solution of 6-fluoroquinoxalin-2(1H)one (1 g, 6.0 mmol) in N,N-dimethylformamide (6 ml) under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again and a solution of 2-(2-bromoethyl)-1,3-dioxolane (0.88 ml, 7.3 mmol) in N,N-dimethylformamide (2 ml) was gradually added thereto and the mixture was stirred for 4 hours. Water was added thereto, the mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 0.5 g (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18]([O:23]C)=[N:19][CH:20]=[CH:21][CH:22]=1.S(Cl)(Cl)=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ncccc1CCN1CCCCC1CC(=O)NCc1cccc(F)c1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(CC1CCCCN1CCc1ccc[nH]c1=O)NCc1cccc(F)c1
Yield: 92.6 %

Procedure:
370 mg of N1-(3-fluorobenzyl)-2-[1-[2-(2-methoxy-3-pyridyl)ethyl]-2-piperidyl]acetamide obtained in Example 177, 0.44 ml of thionyl chloride and 5 ml of ethanol were stirred at 100° C. for 2 hours. The solvent was evaporated, and to the residue was added an aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and dried over sodium sulfate. Then the drying agent was filtered off, and the solvent was evaporated, to give 330 mg of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:11](=[O:22])[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[C:10]1[S:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]1=[O:22]
Reactant: O=C1CSC(c2cccc(Cl)c2)N1CCCN1CCCCC1
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1C(=Cc2cccc(Cl)c2)SC(c2cccc(Cl)c2)N1CCCN1CCCCC1
Temperature: 60 °C

Procedure:
2-( 3-Chlorophenyl)-3-(3-piperidin-1-ylpropyl)-thiazolidin-4-one (3 mm, 1 g), 3-chlorobenzaldehyde (4.5 mm, 0.51 mL), and potassium t-butoxide (4.5 mm, 0.5 g) are mixed in 50 mL toluene with molecular sieves and heated at 60° C. for 4 hours. The molecular sieves are removed by filtration, and the solvent is concentrated to dryness. Pure Compound 2 (0.5 g) is isolated by column chromatography (5% MeOH/CH2Cl2). MS: m/z (APCI, AP+) 462 [M]+. MP 137-139° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([NH:25][CH3:24])=[N:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 80.1.1) to give the title compound as a white solid. (HPLC: tR 2.18 min (Method A); M+H=401 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.49-8.34 (s, br, 2H), 8.13-8.11 (m, 1H), 8.07-8.04 (m, 1H), 7.89-7.85 (m, 1H), 7.42-7.37 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 2.84 (d, 3H), 1.96 (s, 3H))
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][C:3]1=[O:11].[CH3:12]I.[H-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:12])[C:3]1=[O:11]
Reactant: CI
Reactant: COC(=O)C1CN(C)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CN(C)C(=O)N1C
Temperature: -10 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
Methyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (1 g, 6.32 mmol) (prepared as described in step (iii) of Example 1, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) was dissolved in anhydrous tetrahydrofuran (10 ml), cooled to −10° C. under argon, and treated with methyl iodide (1.57 ml, 25.3 mmol). Sodium hydride (60% in oil, 0.24 g, 6.0 mmol) was then added in portions over a period of 15 minutes and the mixture was allowed to warm to room temperature and stirred for 18 hrs. The reaction mixture was then reduced in vacuo and the residue partitioned between ethyl acetate (40 ml) and brine (20 ml). The organic layer was separated, passed through a hydrophobic frit, and reduced in vacuo to give a yellow oil. This material was purified by automated flash silica gel column chromatography (Biotage SP4), eluting with 50% ethyl acetate in hexane (5 column volumes) and then with a gradient of 50-80% in hexane (15 column volumes), to give methyl 1,3-dimethyl-2-oxo-4-imidazolidinecarboxylate (0.479 g) as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:5]=2[N:4]=[CH:3]1.[C:18]12([CH2:28][C:29](Cl)=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[C:18]12([CH2:28][C:29]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[S:11][C:5]=4[N:4]=[CH:3]3)=[O:30])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: Nn1cnc2sc(-c3ccccc3)cc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2sc(-c3ccccc3)cc2c1=O

Procedure:
3-Amino-6-phenylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.75 (m, 12H), 2.01-2.05 (m, 3H), 2.23 (s, 2H), 7.35-7.46 (m, 3H), 7.63-7.65 (m, 2H), 7.69 (s, 1H), 7.99 (s, 1H), 8.10 (s, 1H); MS (DCI/NH3) m/z 420 (M+H)+; Elemental Analysis: Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02. Found: C, 68.53; H, 5.65; N, 9.98.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.[CH3:20][S+](C)(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=O>CS(C)=O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:16])[CH2:4][C:3]1([C:2]([F:1])([F:18])[F:19])[CH2:20][O:17]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(CC2(C(F)(F)F)CO2)CCOc2ccc(F)cc21
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 950 mg (3.45 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one in 10 mL of anhydrous DMSO was added 3.5 mL (4.2 mmol) of a 1.2 M solution of trimethylsulfoxonium ylide, which was prepared by reacting 1.45 g (36.3 mmol) of sodium hydride (60% in mineral oil) with 8 g (36.3 mmol) of trimethylsulfoxonium iodide in 30 mL of DMSO. After 2 hours, the mixture was poured onto ice-cold saturated aqueous ammonium chloride and extracted with 150 mL of ether in several portions. The combined organic layers were washed with four portions of water, then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 930 mg (93%) of 6-fluoro-4-methyl-4(2-trifloromethyloxiranylmethyl)chroman as a 1:1 mixture of diastereomers by 1H NMR.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>Cl>[C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: COC(=O)[C@@H](N)Cc1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccc(I)cc1)NC(C)=O
Temperature: 0 °C
Yield: 56 %

Procedure:
To a solution of 93 (2.25 g, 6.80 mmol) in 10% HCl (10 mL) at 0° C. was added 4M sodium acetate (115 mL) and the resulting reaction was allowed to stir whilst equilibrating to 0° C. Acetic anhydride (50 mL) was added and the reaction allowed to proceed with vigorous stirring. After 1 h the product was collected by vacuum filtration, dissolved in ethyl acetate (30 mL) and washed with 2M sodium bicarbonate (2×30 mL). The organic layer was dried and evaporated to yield the title compound (1.31 g, 3.79 mmol, 56%) as a white solid. Mp 118-120° C. [α]D)27+93.8 (c. 0.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.61 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.84 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′); 5.92 (d, J=7.2 Hz, 1H, NH); 4.87 (m, 1H, H2); 3.73 (s, 3H, OCH3); 3.11 (dd, J=6.0, 13.8, Hz, 1H, H3a); 3.03 (dd, J=5.4, 13.8 Hz, 1H, H3b); 1.99 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 348 (100%) [MH+]. HRMS calcd for C12H15NO3I 348.0097, found 348.0104.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[CH:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[C:10]([C:16]([CH2:18]Cl)=[O:17])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:18][C:16]([C:10]2[CH:9]=[CH:8][C:13]([F:14])=[CH:12][C:11]=2[F:15])=[O:17])[N:3]=1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: Brc1n[nH]c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cn1nc(Br)nc1Br)c1ccc(F)cc1F
Yield: 86.9 %

Procedure:
First, 43.7 g of 3,5-dibromo-1H-1,2,4-triazole is introduced into 200 mL of tetrahydrofuran (THF), the resultant mixture is agitated, and 40.4 g of 2-chloro-2,4-difluoroacetophenone is further introduced thereto. Next, 36.3 g of potassium carbonate is introduced to the reaction mixture and the resultant mixture is agitated for 7 hours at room temperature. After the completion of the reaction, the reaction mixture is filtered, washed with 100 mL of tetrahydrofuran (THF), and concentrated at room temperature. Then, 437 mL of purified water is introduced so that the crystals are slurried, followed by filtering. The filtered crystals are reslurried in 175 mL of isopropanol and filtered again. The crystals are washed with 44 mL of isopropanol and dried with hot air at 50° C. to obtain 63.8 g of the title compound as a white solid (yield 87%, purity 99.2%, HPLC, detected at a wavelength of 256 nm, 18C 4.6×250 mm, mobile phase 60% ACN, flow rate 1 mL/min).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([N:26]=[N+:27]=[N-:28])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N=[N+]=[N-])cc(-n2cnc3ccccc32)n1)c1ccccc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a solution of of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (EXAMPLE 306 Step B) (55.8 mg, 0.16 mmol) in DMF (1 mL) was added sodium azide (16 mg, 0.24 mmol) and the mixture was heated at 80° C. for 7 h. It was cooled and diluted with EtOAc, then the organic layer was washed with H2O followed by brine. The organic extract was dried over Na2SO4, and the crude material was purified by flash chromatography using 1:3 EtOAc:hexane to yield 48.8 mg of the title compound. Mass spectrum 357.1 (CI, M+1).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
88.9 g (196 mmol) 2-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-isoindol-1,3-dione are suspended in 1000 ml ethanol and added to 22.0 g (440 mmol) hydrazine hydrate and heated to boiling for four hours. After cooling, the mixture is filtered and the solvent is removed under vacuum. The solid residue is dispersed in the heat together with the filter residue between 300 ml 10% sodium hydroxide solution and 300 ml acetic acid ethyl ester. The aqueous phase is extracted once with 150 ml warm acetic acid ethyl ester. The combined organic phases are extracted twice, each with 300 ml 10% hydrochloric acid. The combined aqueous phases are made basic with 10% sodium hydroxide solution and extracted twice, each with 400 ml acetic acid ethyl ester. The combined organic phases are washed with 100 ml water and dried over sodium sulfate. The solvent is removed under vacuum, the residue is dried under high-vacuum and processed further without additional purification. Yield of a gradually hardening resin: 63 g (99%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([NH2:38])=[O:37]>>[OH:32][C:29]([CH3:31])([CH3:30])[CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:41][CH2:40][CH2:39][C@H:35]4[C:36]([NH2:38])=[O:37])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](c1ccc(-c2ccc(F)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(N3CCC[C@H]3C(N)=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 30 %

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and L-prolinamide following a procedure analogous to that described in Example 53. Yield: 30% of theory; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][O:27][NH:28][CH3:29]>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:28]([O:27][CH3:26])[CH3:29])=[O:9]
Reactant: COc1ncc(F)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ncc(F)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.7 %

Procedure:
To a solution of 5-fluoro-2-methoxynicotinic acid (1 g, 5.8 mmol) in tetrahydrofuran (10 mL) was added 1,1′-carbonyldiimidazole (1.4 g, 8.77 mmol, 1.5 eq.) portionwise over a 5 min period. The resulting solution was stirred at room temperature for 20 min before adding O,N-Dimethyl-hydroxylamine hydrochloride (0.63 g, 6.43 mmol, 1.1 eq.) and then stirred for a further 72 hr. The resulting mixture was then partitioned between ethyl acetate (30 mL) and 2M aqueous hydrochloric acid (30 mL). The organic phase was washed with 1M aqueous sodium hydrogen carbonate (30 mL), followed by brine (30 mL) and then dried over magnesium sulphate. The resulting mixture was filtered and concentrated under reduced pressure to produce the title compound as a colourless oil (0.53 g, 43%). 1H NMR (400 MHz, CDCl3): δ ppm 3.36 (br. s., 3H) 3.55 (br. s., 3H) 3.97 (s, 3H) 7.33-7.44 (m, 1H) 8.06 (d, J=2.73 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].I[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:28])[CH3:29])=[O:25])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCCI
Product: CCOCc1nc2cnc3cc(OCCCCCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Yield: 92.3 %

Procedure:
Following the method described in Part L of Example 2, N-{2-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (3.12 g, 7.80 mmol) was treated with tert-butyl 6-iodohexylcarbamate (2.81 g, 8.58 mmol) to afford 4.31 g of tert-butyl 6-{[2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate. The material was used without purification in the next step.