Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Reactant: Nc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) and a few drops of DMF (0.05 mL) was heated with stirring at 90° C. for 3 hours. The solvents were then evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then 3-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (3-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.4 g, 56%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([C:13]3[C:17]([CH:18]=O)=[CH:16][NH:15][N:14]=3)[CH:11]=[CH:12][C:4]=2[O:3]1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1>C(Cl)Cl.CO.C(O)(=O)C>[F:36][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:18][C:17]3[C:13]([C:10]4[CH:11]=[CH:12][C:4]5[O:3][C:2](=[O:1])[NH:7][C:6](=[O:8])[C:5]=5[CH:9]=4)=[N:14][NH:15][CH:16]=3)[CH2:30][CH2:29]2)=[N:26][CH:27]=1
Reactant: O=Cc1c[nH]nc1-c1ccc2oc(=O)[nH]c(=O)c2c1
Reactant: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=O)c2cc(-c3n[nH]cc3CN3CCCN(c4ccc(C(F)(F)F)cn4)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 3-(2,4-dioxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-pyrazole-4-carbaldehyde (51.4 mg, 0.2 mmol) and 1-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepane (24.5 mg, 0.1 mmol) in methylene chloride (1.0 mL), methanol (0.5 mL) and acetic acid (15 μL) is stirred for 30 minutes at room temperature. Then Na(AcO)3BH (84 mg, 4.0 equiv.) is added and the reaction is stirred overnight at room temperature. After evaporation, the residue is redissolved in DMF (1.0 mL) which is subject to reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90% CH3CN in 7.5 min, Ultro 120 5 uM C18Q, 75×30 mmID) The collected water/MeCN solution of the TFA salt of the product is evaporated to remove the acetonitrile. A saturated aqueous solution of NaHCO3 is added to raise the pH to about 8-9. Then ethyl acetate is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yields the free-based 6-{4-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-ylmethyl]-1H-pyrazol-3-yl}-benzo[e][1,3]oxazine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
36.2 g of 3-bromopyridone (87% purity, 0.18 mol) and 29.4 g of 4-fluoro-3-methoxynitrobenzene (0.17 mol) were introduced as initial charge in 180 ml of N-methylpyrrolidone; 46.1 g of anhydrous potassium phosphate (0.22 mol) were added and the reaction mixture was carried out at 120° C. for 6 h. After cooling to 90° C., water was added and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and stirred with a methanol/water mixture (1:1). The solid was filtered off, washed and dried in the air. This gave 38.7 g (66%) of the desired target compound.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22]C)=[O:21])[CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]/[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)C>CO.[OH-].[Na+]>[C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([C:11]1[CH:10]=[CH:9][C:8]([O:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]/[C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:40])=[O:3])=[O:24])([OH:22])=[O:21]
Reactant: CCOC(=O)COc1cc(C(=O)c2cccc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/CCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2OCC(=O)O)cc1
Yield: 79.4 %

Procedure:
Under the conditions of example 1B, 30 mg of 5-(3-methoxycarbonylbenzoyl)-2-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenoxy acetic acid ethyl ester is saponified in 1 ml of methanol with 1 ml of In sodium hydroxide solution and worked up. 22 mg of 5-(3-carboxybenzoyl)-2-[6-(4-methoxyphenyl)-(5E)-5hexenyloxy]-phenoxy acetic acid is obtained as colorless oil.
Reaction SMILES: Br[CH:2]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([F:17])([F:16])[C:8]([F:19])([F:18])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]1=2)[CH2:3][CH3:4].[NH3:24]>>[F:19][C:8]1([F:18])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[CH:5]([CH2:2][CH2:3][CH2:4][NH2:24])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]1([F:17])[F:16]
Reactant: CCC(Br)C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reactant: N
Product: NCCCC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
A mixture of 1 gram of 5-(1-bromopropyl)-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene and 20 ml. of liquid ammonia is heated in a sealed tube at 100°C. for 8 hours. After cooling, the ammonia is allowed to evaporate at room temperature and the residual product diluted with ether and the ethereal solution of the product washed with water, dried, and concentrated to leave as a residue 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20](O)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:17][CH2:16][C:15]([CH2:20][OH:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC12CCC(CO)(CC1)CC2)OCc1ccccc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
4-Benzyloxycarbonylaminobicyclo[2,2,2]octane-1-carboxylic acid (500 mg) was dissolved in tetrahydrofuran (8 mL). While the solution was chilled in a salt/ice bath, N-methylmorpholine (0.18 mL) was added. This was followed by dropwise addition of ethyl chlorocarbonate (0.16 mL) and stirring for 10 minutes. To the reaction mixture, sodium borohydride (187 mg) and then methanol (15 mL) were added and the mixture was stirred below 0° C. for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water was added and the solution was extracted with ethyl acetate. The ethyl acetate layer was then washed sequentially with 1 mol/L hydrochloric acid and water, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluant: hexane: ethyl acetate=1:1) to obtain 4-benzyloxycarbonylamino-1-hydroxymethylbicyclo[2,2,2]octane (453 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(#N)C>[ClH:2].[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH:33][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Temperature: 60 °C
Yield: 65.8 %

Procedure:
HCl (1.0 ml, 4M solution in dioxane) was added to 4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yloxy]quinazoline (0.786 g) and 3-chloro-2-fluoroaniline (0.304 g) dissolved in acetonitrile (25 ml). The mixture was heated to 60° C. for 2 hours, cooled and the precipitate collected to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride as a white solid (0.577 g, 66%); 1H NMR Spectrum: (DMSOd6) 1.70-1.95 (m, 2H), 1.95-2.10 (m, 1H); 2.10-2.25 (m, 1H), 2.95-3.10 (m, 1H), 3.10-3.30 (m, 2H), 3.45-3.65 (m, 1H); 4.03 (s, 3H); 4.95-5.10 (m, 1H); 7.30-7.45 (m, 1H); 7.45-7.60 (m, 2H); 7.60-7.73 (m, 1H), 8.85 (s, 1H); 8.90 (s, 1H); 9.15 (bs, 2H); 12.3 (bs, 1H); Mass Spectrum: (M+H): 403.
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.1 g of 17-(cyclopropylimino)androst5-en-3β-ol in 200 ml of dry ethanol was added 2 g of sodium borohydride. The reaction mixture was stirred at room temperature for 3 hours and then 100 ml of solvent was removed from the mixture under reduced pressure The reaction mixture was then quenched with dilute acetic acid, diluted with 600 ml of water, and the pH was adjusted to 14 by the addition of sodium hydroxide. The aqueous mixture was extracted 3 times with 600 ml potions of ethyl acetate and the combined organic extracts were dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the desired 17β-(cyclopropylamino)androst-5-en-3β-ol as a white solid; MS (m/z): 370 (M+41)+, 358 (M+29)+, 330(M+H)+, 312 (MH-H2O)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 93.3 %

Procedure:
To a stirred solution of 2-naphthyl carboxylic acid (76.5 g, 0.45 mol) in dichloromethane (500 ml) was added thionyl chloride (38.7 ml, 0.53 mol) and the mixture was heated at reflux temperature for 48 h. The volatiles were evaporated in vacuo affording 80 g (94%) of 2-naphthoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2-chloro-3-fluorobenzoic acid (3.32 g, 19.02 mmol) in DMF (60 mL) was added N,O-dimethylhydroxylamine hydrochloride, 98% (2.30 g, 23.58 mmol), O-(-7-azabenzotriazol-1-yl)-N,′N,′N,′N′-tetramethyluronium-hexafluorophosphate (HATU) (8.82 g, 23.20 mmol) and triethylamine (6.63 mL, 47.5 mmol). The mixture was stirred at rt for 3 h. The reaction was quenched with saturated Na2CO3 and extracted with EtOAc. The organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (80 g, 10-100% EtOAc/hexane in 25 min) to give 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide as colorless oil, which turned to solid on vacuum (3.95 g, 95% yield). MS m/z=218 [M+H]+. Calculated for C9H9ClFNO2: 217.6.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:12])([F:11])[F:10])([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 1.52 g of magnesium in 25 ml of THF is admixed dropwise over 20 minutes with a solution of 14.25 g of 1-bromo-2-(trifluoromethyl)benzene in 15 ml of THF and the mixture is heated at reflux for 30 minutes. After it has cooled on an ice bath, it is admixed slowly with a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF and left with stirring at AT for 3 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution and extracted with AcOEt, the combined organic phases are washed with water and dried over Na2SO4 and the solvents are evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (70/30; v/v) mixture. This gives 4.5 g of the expected product.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:4][C:3]=2[O:2]1.[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]=2[O:2]1
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)=CCCc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: c1ccccc1
Product: CC(C)CCCC(C)CCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 g. of 9-(3,4-methylenedioxyphenyl)-2,6-dimethyl-2,6-nonadiene (prepared as in Example 8) in 40 ml. of benzene was added 2.0 g. of a 5 percent palladium on carbon catalyst. Hydrogen was introduced into the reaction vessel to a pressure of 50 psig. This mixture was shaken at room temperature for 16 hours. The catalyst was removed by filtration and the benzene was evaporated under reduced pressure to yield pure 9-(3,4-methylenedioxyphenyl)-2,6-dimethylnonane (XI). The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[NH:27][N:26]=2)=[CH:21][CH:20]=1.O>C(#N)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[N:27]([CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
4.19 g of 3-nitrobenzyl bromide and 9.95 g of potassium carbonate are added to a solution of 4.00 g of 5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one in 80 ml of acetonitrile, and the mixture is stirred at 80° for a further 2 h. The mixture is poured into water, extracted 2× with diethyl ether, dried, filtered and evaporated to dryness. A little diethyl ether is added to the residue, which is crystallised and dried in a vacuum drying cabinet at 50° C., giving 5.5 g (86%) of 5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27].Br(Br)(Br)Br>>[CH3:19][C:9]1([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][O:25][C:26]3=[O:27])[C:11]([OH:18])([C:14]([F:15])([F:17])[F:16])[CH2:10]1
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2c1COC2=O
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1COC2=O
Yield: 19 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-aminophthalide. By reaction of 640 mg of the imine with 7.7 ml of bromine tribromide solution (1 M in dichloromethane), 165 mg of 4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide is obtained as fraction 1, and 115 mg of 4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide is obtained as fraction 2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(Br)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27 mmol) and dichloromethane (40.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)+; Retention time: 1.37 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=NC2N(N=CN=2)[C:3]=1O.[OH-].[Na+].C1[C@H](N[C@H:22]2[C@H:27](O)[C@@H:26](O)[C@@H:25]([O:30][C@@H:31]([C@H:36]([OH:41])[C@@H:37]([OH:40])C=O)[C@H](O)CO)[O:24][C@@H:23]2[CH2:42]O)[C@H](O)[C@@H](O)[C@H](O)C=1CO.B(O)(O)O>O>[CH3:11][CH2:10][CH2:2][CH2:3][CH2:42][CH2:23][CH2:22][CH2:27][CH2:26][CH2:25][CH2:42][CH2:23][CH2:22][CH2:27][CH2:26][C:25]([O:30][CH2:31][CH:36]([OH:41])[CH2:37][OH:40])=[O:24]
Reactant: Cc1nc2ncnn2c(O)c1Br
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO)[C@@H](N[C@H]2C=C(CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)CO
Agent: OB(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Component D: A mixture of 5-bromo-4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene, water, and 2.5N NaOH was placed in a beaker and heated to 50° C. to dissolve the materials and form Compound TAI-1. A mixture of boric acid and the indicated thermal solvent was dissolved in water by heating at 50° C. The solution was cooled to room temperature and a portion of deionized lime-processed gelatin was added to the solution to be hydrated for 30 minutes. The mixture was heated to 40° C. for 10 minutes to melt the gelatin. A portion of a dispersion of 6.5 μm polystyrene beads in gelatin was placed in another beaker and heated to 40° C. for 10 minutes to melt the gelatin. The two gelatin containing subcomponents were combined and the mixture was added a 4% active aqueous solution of ZONYL® FS-300 surfactant and a portion of the Compound TAI-1 solution described above.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:26]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(CC(F)(F)F)c1ncc(N)cn1
Product: CN(CC(F)(F)F)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}-amide was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-Methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine. LCMS calcd for C18H13F6N5O2 (m/e) 445, obsd 446 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12]Br)[CH:6]=1)[CH3:2].[CH2:15]([O:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:24]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:25][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)c(CBr)c1
Reactant: CCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-3-bromomethyl-benzoic acid ethyl ester (2.95 g, 9.2 mmol) and ethyl-carbamic acid benzyl ester (3.30 g, 18.4 mmol) were combined in DMF (100 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 0.772 g, 19.3 mmol) was added slowly, and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H2O and 1N aqueous HCl (20 mL), and then extracted with 1:1 EtOAc:hexanes three times. The organic layer was washed with brine, and then dried and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester, as well as the hydrolyzed product, which was combined with the product from the next step.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)C(OCC)=O)C.Cl.N1C=CC(CCCC(O)=O)=CC=1>>[NH:16]1[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][CH2:5][C:4]([OH:19])=[O:3])[CH2:14][CH2:15]1
Reactant: CCOC(=O)C(CCc1ccncc1)C(=O)OCC
Agent: Cl
Agent: O=C(O)CCCc1ccncc1
Product: O=C(O)CCCC1CCNCC1

Procedure:
In an especially preferred preparation of VIII, 2-(4-pyridyl)ethylmalonic acid diethyl ester is taken up in aqueous acid, preferably aqueous HCl, and decarboxylated by heating at reflux. A catalyst as described above is then added to the resulting solution of 4-(4-pyridyl)butanoic acid XIII and the mixture is catalytically hydrogenated to give an aqueous solution of 4-(4-piperidyl)butanoic acid XIV. The catalyst is then filtered off, the acidic solution of XIV is made basic with aqueous alkoxide and the benzyloxycarbonyl protecting group is introduced as described above. The 1-[(phenylmethoxy)carbonyl]-4-piperidinebutanoic acid is then extracted into an organic solvent and condensed with N-ethylglycine as described above to give VIII.