Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(C(NC[C@H](N2CCN(S(C)(=O)=O)CC2)C(OC)=O)=O)=CC=1.BrCC1C2C(=CC=CC=2)C=CC=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][N:46]([C@@H:49]([CH2:54][NH:55][C:56](=[O:76])[C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]3[C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)N=[C:67]([CH3:75])[CH:66]=3)=[CH:59][CH:58]=2)[C:50]([O:52][CH3:53])=[O:51])[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][N:46]([C@@H:49]([CH2:54][NH:55][C:56](=[O:76])[C:57]2[CH:58]=[CH:59][C:60]([O:63][CH2:64][C:65]3[C:74]4[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH:75]=[CH:67][CH:66]=3)=[CH:61][CH:62]=2)[C:50]([O:52][CH3:53])=[O:51])[CH2:45][CH2:44]1)(=[O:41])=[O:42]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: BrCc1cccc2ccccc12
Agent: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2cccc3ccccc23)cc1)N1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner similar to example 4-5, starting from 300 mg (0.8 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)-propanoate (prepared as described in example 4-4) and from 200 mg (1.2 mmol) of 1-bromomethylnaphthalene, 320 mg (78%) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzoylamino]-propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
153.8 mg of the target compound (0.45 mmol, 54.9%) was obtained using 1-(3-methylphenyl)piperazine (289 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:21]#[N:22])C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc2cc[nH]c12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc2c(C=O)c[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
DMF (0.539 mL) in dry dichloromethane (30 mL) was added dropwise to a solution of oxalyl chloride (0.610 mL) in dry dichloromethane (30 mL) at 0° C. The resulting solution was stirred at 0° C. for 15 min. A solution of 1H-indole-7-carbonitrile (D2) (0.90 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred for 30 min. The solvent was evaporated. THF (20 mL) was added, followed by addition of aqueous NaOH (0.5 M, 50 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (100 mL) and water (70 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-7-carbonitrile (D3) as a light cream solid (0.75 g, 70%). δH (DMSO-d6, 400 MHz): 7.42 (1H, t), 7.79 (1H, dd), 8.43 (1H, dd), 8.48 (1H, s), 10.00 (1H, s), 13.02 (1H, br s). MS (ES): C10H6N2O requires 170; found 171.2 (M+H+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:22][CH3:23])[C:11]([C:13]([N:15]([CH:19]3[CH2:21][CH2:20]3)[CH:16]3[CH2:18][CH2:17]3)=[O:14])=[CH:12][C:7]2=[C:6]2[N:24]([CH3:27])[CH:25]=[N:26][C:5]=12.[CH3:28][O:29][CH:30]([O:39][CH3:40])[C:31](=[O:38])[CH:32]=[C:33](SC)[S:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH:16]1([N:15]([CH:19]2[CH2:21][CH2:20]2)[C:13]([C:11]2[N:10]([CH2:22][CH3:23])[C:8]3=[N:9][C:4]([NH:3]/[C:33](/[S:34][CH3:35])=[CH:32]/[C:31](=[O:38])[CH:30]([O:29][CH3:28])[O:39][CH3:40])=[C:5]4[N:26]=[CH:25][N:24]([CH3:27])[C:6]4=[C:7]3[CH:12]=2)=[O:14])[CH2:18][CH2:17]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: COC(OC)C(=O)C=C(SC)SC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Sodium hydride (142 mg, 3.55 mmol) was added to 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 400 mg, 1.182 mmol) in DMF (7 mL) at room temperature and the mixture stirred for 30 min, 1,1-dimethoxy-4,4-bis(methylthio)but-3-en-2-one (394 mg, 1.773 mmol) was added and stirring continued overnight. The reaction mixture was diluted with ethyl acetate and washed with water, 10% lithium chloride and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 2-5% methanol/dichloromethane). (Z)-N,N-Dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (484 mg, 0.944 mmol, 80% yield) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:7]1.C([OH:38])(CC)(C)C.[OH-].[K+]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]([NH2:15])=[O:38])[CH2:7]1
Reactant: CCC(C)(C)O
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC(Oc2cccc(O)c2)C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2cccc(O)c2)C1
Temperature: 80 °C

Procedure:
A suspension of 5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenyl-hexanenitrile (0.16 g, 0.38 mmol, 1 equiv), t-amyl alcohol (1.8 ml, 12 ml/g) and KOH (0.41 g, 7.26 mmol, 20 equiv) was heated to 80° C. for 2 d whereupon HPLC showed completion of reaction. The reaction was cooled to ambient then partitioned between water and TBME, the aqueous layer was acidified to pH 8 with aq HCl, layers separated and the organic layer concentrated to afford 5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide as a colourless oil, 0.11 g (68%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:23]=[C:22]([CH3:24])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:25])[CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:23]=[C:22]([CH3:24])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[N+:18]([O-:33])[CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:25])[CH:9]=2)[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccnc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc[n+]([O-])c1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine (1 g, 2.6 mmol) in 50 ml of methylene chloride cooled to 0° C. was added 0.67 g (3.9 mmol) of m-chloroperoxybenzoic acid, and the mixture was allowed to stir overnight. The mixture was washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1 g (98%) of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide, as a yellow oil which crystallized (yellow flakes) on standing, m.p. 84°-86°C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[F:24]NS(C1C=CC=CC=1)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[F:24]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=S(=O)(NF)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1F
Reaction time: 48 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-fluorobenzenesulphonamide (259 mg, 0.822 mmol), and DMF (4 mL) were warmed to 90° C. behind an explosion shield. After 48 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate:hexane 1:1) to afford 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28): Mass Spectrum (CI) 323 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:14]>C(Cl)Cl>[O:5]([CH2:6][CH:7]1[CH2:8][O:14]1)[CH2:1][CH:2]1[CH2:3][O:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCC1CO1
Solvent: ClCCl
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 156.8 %

Procedure:
28.54 g of allyl glycidyl ether (0.15 mole) (Aldrich) is dissolved in 1000 ml of methylene chloride and cooled to 0° in an ice bath. In one single addition 51.75 g of m-chloroperoxybenzoic acid (1.05 equiv. @ 85% tech) (Aldrich) is added and the reaction stirred rapidly at 0° for 4 hours. The reaction is allowed to slowly warm to room temperature and stirred overnight. The precipitated m-chlorobenzoic acid is removed via filtration and washed with 50 ml of cold CH2Cl2. The CH2Cl2 solution is then washed with 2×200 ml of saturated potassium carbonate solution and dried over Na2SO4. The CH2Cl2 is removed in vacuo yielding 30.6 g (94%) of 2,2'-(oxybismethylene)bisoxirane as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.O[C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([CH3:27])[CH:15]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:12][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCC(O)c1cccc(Br)n1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-butanol (626 mg, 2.72 mmol) and ethyl (4-hydroxy-2-methylphenoxy)acetate (539 mg, 2.56 mmol) in dry THF (51 mL) at 0° C. (ice/water bath) under nitrogen was added ADDM (1.32 g, 5.13 mmol) followed by nBu3P (1.28 mL, 4.95 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3×75 mL), dried (Na2SO4), filtered and reduced to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 10:1) afforded the title compound (388 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH:17](Br)([CH3:19])[CH3:18].[OH-].[K+]>COCCOC>[CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=1)=[O:6]
Reactant: CC(C)COC(=O)c1n[nH]c2ccccc12
Reactant: CC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)COC(=O)c1nn(C(C)C)c2ccccc12
Yield: 36.8 %

Procedure:
To a solution of 2-methylpropyl-1H-3-indazolecarboxylate (50 g; 0.24 moles) in 1,2-dimethoxy-ethane (300 ml) a solution of isopropyl bromide (27.5 ml; 0.29 moles) in 1,2-dimethoxy-ethane (100 ml) and KOH (13.5 g; 0.24 moles) was added and the mixture was heated under reflux for 8 hours. After removal of the solvent, the residue was dissolved in toluene (300 ml), the thus obtained solution was washed with 1N NaOH (100 ml), H2O (2×100 ml) and then dried and concentrated in vacuum. The residue was purified from the isomer 2-methylpropyl-2-isopropyl-2H-3-indazolecarboxylate via flash chromatography (eluent, hexane:ethyl acetate=95:5) to give the title compound (23 g) as an oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][CH:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(#N)C>[NH2:2][C:3]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][I:20])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCCCCCCCCCCCCCC(I)I
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(N)(CCCCCCCCCCCCCCCCI)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethyl 2-aminomalonate hydrochloride (2.116 g, 10.0 mmol) and caesiumcarbonate (7.100 g, 21.8 mmol, 2.2 eq.) were suspended in acetonitrile (50 mL) and stirred at r.t. for 15 min. Then diiodohexadecane 28 (5.017 g, 10.5 mmol, 1.1 eq.) was added and the mixture was refluxed for 6 h. After cooling to r.t. and partial evaporation of the solvent, the residue was purified by column chromatography (silica gel, 16×4 cm, cyclohexane/ethyl acetate, 2:1) to give the product as a yellowish oil. Yield: 3.097 g (56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[S:16]([N:19]=C=O)(=[O:18])=[O:17].C1(C)C=CC=CC=1>C1C=CC=CC=1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:16](=[O:18])(=[O:17])[NH2:19])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 10.4 g (0.05 mole) of 5-hydroxy-2-nitrobenzotrifluoride, 7.8 g (0.055 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.1 g (78%) of tan solid, mp 95°-97° C. (benzene).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CN(C=O)C.O>[F:3][C:4]([F:9])([F:8])[CH:5]([O:7][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH3:6]
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Sodium hydride (297 mg, 12.4 mmol) was suspended in DMF (3 ml) at 0° C. 1,1,1-trifluoropropan-2-ol (500 μl, 5.52 mmol) was added slowly and the reaction was stirred for 15 minutes at 0° C. before addition of 4-fluorobenzonitrile (500 mg, 4.13 mmol). The mixture was allowed to reach room temperature and was then stirred at 50° C. for 20 hours. The reaction was cooled, diluted with water (75 ml) and extracted with EtOAc (4*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (8:1) as eluent to give 690 mg (78%) of the title compound as a clear liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg]I>CCOCC>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH3:16])[C@:10]([CH3:24])([OH:15])[C:11]([F:14])([F:12])[F:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](C(=O)C(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]I
Solvent: CCOCC
Product: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)[C@](C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(R)-3-(Dibenzylamino)-1,1,1-trifluorobutan-2-one (Example 52A) (3.41 g, 10.61 mmol) was dissolved in Et2O (80 mL) and then cooled to ca. 0° C. (ice external temp) prior to the addition of MeMgI (7.07 mL, 3 M). Addition of the Grignard reagent caused the reaction to become heterogeneous. After stirring for 10 min, TLC indicated good conversion to a slightly less polar than sm product (a trace of what appeared to be sm remained), the mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic portions were dried over Na2SO4 and concentrated. The resulting bright yellow residue was purified by flash chromatography (ISCO, 80 g silica, 0% to 40% over 27 min. ca. 10 min ret time; hex/EtOAc) to afford the desired product as a bright yellow oil. TLC, LCMS, and NMR showed ca.15-20% of the bis CF3 alcohol contaminating the desired product. A trace of the other diastereomer also existed. The material was concentrated and rechromatographed (straight CH2Cl2, 80 g SiO2, 254/230 nm) to afford separation of the bis-CF3 alcohol and desired product (1.94 g, 54%). This material was used in its entirety for the debenzylation step: 1H NMR (400 MHz, DMSO-d6) δ 7.62-7.48 (m, 10H), 6.11 (s, 1H), 4.16 (d, J=13.6 Hz, 2H), 3.61 (d, J=13.7 Hz, 2H), 3.15 (q, J=6.8 Hz, 1H), 1.42-1.40 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C1COCC1.[CH2:26]([O:28][C:29](=[O:34])[C:30](=O)[CH2:31]Br)[CH3:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:26]([O:28][C:29]([C:30]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:31]=1)=[O:34])[CH3:27]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-(4-trifluoromethyl-phenyl)-acrylamide (5.0 g, 23.2 mmol) and NaHCO3 (7.80 g, 92.9 mmol) in THF (90 ml) 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added under an argon atmosphere. The mixture is heated to reflux for 15 h when another portion of 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added and stirring continued for 5 h. After cooling to r.t. the mixture is filtered, concentrated in vacuo and the resulting residue suspended in THF (20 ml). At 0° C. trifluoroacetic acid anhydride (16.3 g, 77.9 mmol) is added and the mixture stirred at room temperature for 16 h. The mixture is neutralized with sat. NaHCO3, the aqueous layer extracted with ethyl acetate (2×200 ml) and the combined organic phases dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid ethyl ester as a colorless solid. Yield 5.84 g (81%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:32]2[CH2:33][CH2:34][CH:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:30][CH2:31]2)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 80.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (250 mg, 0.70 mmol) in DCM (10 mL) were added 4-(1-pyrrolidinyl)piperidine (323 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (253 mg, 81%). LC-MS m/z 449 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1([CH3:15])[CH2:14][CH2:13][C:6]2([NH:10]C(=O)N[C:7]2=[O:12])[CH2:5][CH2:4]1.[OH-:16].[K+].[ClH:18]>>[ClH:18].[NH2:10][C:6]1([C:7]([OH:12])=[O:16])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:15])[CH2:14][CH2:13]1
Reactant: COC1(C)CCC2(CC1)NC(=O)NC2=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COC1(C)CCC(N)(C(=O)O)CC1

Procedure:
169.5 g of the compound from Example 13A in 970 ml of 30% strength aqueous potassium hydroxide solution were heated under reflux for 20 hours. After cooling, the reaction mixture was adjusted to pH 2 by addition of 670 ml of concentrated aqueous hydrogen chloride solution, the precipitate was filtered off with suction and the filtrate was concentrated. This gave 110.7 g of a crude product as a mixture of diastereomers which still contains salts and was reacted without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)=[CH:24][CH:23]=2)[C:7](=[O:33])[C:6]=1O)=O.O.[NH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:2]([C:3]1[C:5]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)=[CH:24][CH:23]=3)[C:7](=[O:33])[C:6]=2[NH:38][N:39]=1)([CH3:36])([CH3:35])[CH3:1]
Reactant: COC(=O)COc1ccccc1C1C(C(=O)C(C)(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ccccc1C1c2c(C(C)(C)C)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-(2,2-dimethylpropionyl)-3-hydroxy-5-(2-methoxycarbonylmethyloxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.207 g, 0.41 mmol), hydrazine hydrate (0.022 mL, 0.45 mmol) and acetic acid (3.1 mL) was stirred at 95° C. for 1 hour. After the reaction was completed, saturated sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulphate, and then concentrated in vacuo. The resulting residue was triturated with ethyl ether and diisopropyl ether to give 3-t-butyl-5-(4-thiophene-3-ylphenyl)-4-(2-methoxycarbonylmethyloxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.191 g, yield: 93%) as pale brown solid.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O>S(=O)(=O)(O)O.O>[OH:23][C:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])[C:9](=[O:22])[C:10]=2[C:11]([NH2:19])=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: O=S(=O)=O
Agent: OB(O)O
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
30 parts of 1,5-dinitroanthraquinone are stirred in 300 parts of 28% strength oleum for 4 hours at 50° to 60° C. 15 parts of boric acid are then added with cooling and dissolved. The reaction mixture is then diluted with 57.5 parts of 78% sulphuric acid and 156 parts of water, while cooling is continued, and stirred for 15 hours at room temperature. The reaction mixture is discharged onto 2,000 parts of ice, and the product is filtered off with suction and washed with warm water until neutral. After the product has been stirred with 500 parts of a 10% strength aqueous pyridine solution at 90° to 100° C., filtered off with suction and washed, 16 parts of 1-hydroxy-4-amino-8-nitroanthraquinone are obtained.