Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15](CC3C=CC(OC)=CC=3)[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N.O>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCc3ncc(OCc4ccccc4)cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1NCCc2ncc(OCc3ccccc3)cc21
Reaction time: 1 h
Yield: 41.2 %

Procedure:
3-(Benzyloxy)-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.05 g, 2.8 mmol) was dissolved in MeCN (50 mL). To the solution cerium ammonium nitrate (15.4 g, 28 mmol) in water (50 mL) was added slowly at room temperature. The reaction was stirred for 1 h at the same temperature, partitioned between EtOAc (200 mL) and brine (200 mL). The organic layers were dried, concentrated and purified by column chromatography (MeOH, DCM 0-5%). The compound was obtained as an off white solid (293 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.8, 1H), 7.94 (d, J=2.8, 1H), 7.47-7.35 (overlapped, 5H), 6.05 (br s, NH), 5.16 (s, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 3.66 (td, J=6.8, 2.4, 2H), 3.17 (td, J=6.8, 2.4, 2H); LC-MS (M+H)=255.1
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-])=O.[NH2:21][C@H:22]([C:28]([OH:30])=O)[CH2:23][CH2:24][C:25](O)=[O:26]>>[O:11]([S:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][CH:22]1[C:28](=[O:30])[NH:18]2)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: O=C1Nc2cc(S(=O)(=O)Oc3ccccc3)ccc2N2C(=O)CCC12

Procedure:
The compound was obtained in analogous manner by reacting phenyl 4-chloro-3-nitrobenzenesulfonate with L-glutamic acid, melting point 140° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=C1>O.CN(C=O)C>[CH2:35]([NH:42][C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([C:3]2[C:2]([Cl:1])=[C:7]([CH2:8][N:9]3[C:10](=[O:15])[CH2:11][CH2:12][C:13]3=[O:14])[N:6]=[C:5]3[S:16][C:17]4[CH2:22][S:21](=[O:23])[CH2:20][CH2:19][C:18]=4[C:4]=23)=[CH:25][CH:26]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1cnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of the compound obtained in Example 115 (104 mg), benzylamine (24 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 42 mg), 1-hydroxy-1H-benzimidazole monohydrate (HOBt, 34 mg) and DMF (3 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain N-benzyl-2-(4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetamide from the fraction eluted with ethyl acetate-methanol (6:1) (70 mg, 57%). It was recrystallized from THF-hexane. Colorless prisms. Melting point 220–221° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][C:20](OCC)=[O:21])[CH:15]=[CH:16][CH:17]=1.C(Cl)Cl>CCCCCC>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:19][CH:20]=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(c1cccc(Br)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Reaction time: 4 h
Yield: 76 %

Procedure:
Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a −78° C. solution of ethyl 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring for 4 h, the reaction was quenched with cold methanol (300 μL), and then saturated ammonium chloride (500 μL) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with hexane:EtOAc, (2:1 to 1:2), to give 3-(3-bromophenyl)-3-[4-(7-[2-(trimethyl silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (400 mg, 70%) as an oil. 1H NMR (400 MHz, CDCl3): δ□ 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01 (s, 9H). m/z=526, 528 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:5]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(Br)c1O
Solvent: O
Product: O=C(O)c1cc2cccc(Br)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
3-bromohydroxybenzaldehyde (139.5 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 135.0 mg of 8-bromo-3-carboxy-coumarin in an 73% yield.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.S(Cl)([Cl:30])=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:30][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CO)s3)cc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reaction time: 1 h
Yield: 74 %

Procedure:
N-{2-[5-(Hydroxymethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.55 g) was dissolved in absolute tetrahydrofuran (25 ml), and this solution was ice-cooled. Thionyl chloride (0.15 ml) and N,N-dimethylformamide (one drop) were added, and the mixture was stirred for 1 hr under ice-cooling, and then at room temperature for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (0.427 g, yield 74%) as pale-yellow crystals. melting point 194-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10]Br)=[N:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:4].[F:20][C:21]1[C:29]([OH:30])=[CH:28][CH:27]=[C:26]([F:31])[C:22]=1[C:23]([NH2:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][O:30][C:29]2[CH:28]=[CH:27][C:26]([F:31])=[C:22]([C:23](=[O:24])[NH2:25])[C:21]=2[F:20])=[N:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)c1sc(CBr)nc1-c1ccc(OC)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
To a solution of 2-Bromomethyl-4-(4-methoxy-phenyl)-thiazole-5-carboxylic acid methyl ester (0.05 g, 0.14 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.025 g, 0.14 mmol) and potassium carbonate (0.07 g, 0.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.025 g, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 3.76 (s, 3H), 3.81 (s, 3H), 5.60 (s, 2H), 7.01 (d, J=8.40 Hz, 2H), 7.12 (m, 1H), 7.41 (m, 1H), 7.74 (d, J=8.40 Hz, 2H), 7.90 (br s, 1H) and 8.18 (br s, 1H). MS ES+ (435.06), HPLC (method I) Rt=15.86 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>COCCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]1[N:30]=[C:8]([C:3]2[S:4][C:5]([CH3:7])=[N:6][C:2]=2[CH3:1])[CH:9]=[CH:10][N:29]=1
Reactant: N=C(N)Nc1ccc(F)cc1F
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3F)n2)s1
Yield: 78.5 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(2,4-difluoro-phenyl)-guanidine nitrate (2 mmol, 0.47 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). After 24 h refluxing under N2 the solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as a brown powder (250 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Br)cc1Br
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Br)cc1Br

Procedure:
using isopropyl 2,4-dibromo-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dibromo-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 8.03 ppm (s, 1H), 4.72 ppm (s, 1H), 5.23 ppm (m, 1H), 2.96 ppm (m, 2H), 2.83 ppm (m, 2H), 2.17 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].COC1C=CC(C[NH2:33])=CC=1.ClCCl>CN(C=O)C.CO>[NH2:33][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)c1cnc(Cl)c2cc(-c3ccccc3)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc(N)c2cc(-c3ccccc3)sc12
Temperature: 55 °C

Procedure:
To a suspension of 1-(4-chloro-2-phenyl-thieno[3,2-c]pyridin-7-yl)-ethanone 97 (61 mg, 0.21 mmol) and potassium carbonate (174 mg, 1.26 mmol) in DMF (1.8 mL) was added 4-methoxybenzylamine (85 μl, 0.64 mmol). The resultant mixture was heated at 50° C. for 6.75 h. After this time, 20 mL of a 1:1 mixture of dichloromethane and methanol was added and the resultant slurry was filtered. The filtrate was concentrated and the residue was dissolved in trifluoroacetic acid (7 mL). The resultant mixture was heated at 55° C. for 2.75 h. After this time, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: dichloromethane:MeOH:Et3N, 98.5:1.5:0.5) to give 98.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.C=C1C=[CH:70][C:69]2[CH:72]=[C:73]([C:76]([O:78][CH3:79])=[O:77])[CH:74]=[CH:75][C:68]=2[O:67]C1.S(OS([O-])=O)([O-])=O.[Na+].[Na+].[C:89]([OH:93])([CH3:92])([CH3:91])[CH3:90].O>ClCCl>[OH:93][C:89]1([CH2:92][OH:22])[CH:91]=[CH:70][C:69]2[CH:72]=[C:73]([C:76]([O:78][CH3:79])=[O:77])[CH:74]=[CH:75][C:68]=2[O:67][CH2:90]1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=C1C=Cc2cc(C(=O)OC)ccc2OC1
Agent: CS(N)(=O)=O
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(O)(CO)CO2
Reaction time: 96 h
Yield: 100 %

Procedure:
21 g (7 equivalents) of AD-mix-α and 1.31 g (13.8 mmol) of methanesulfonamide dissolved in 75 ml of a 1/1 tert-butyl alcohol/water mixture are added at ambient temperature to 3 g (13.8 mmol) of methyl 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 35, in suspension in 20 ml of a 1/1 tert-butyl alcohol/water mixture. The reaction medium is stirred for 4 days and is then treated with 2.6 g of sodium disulfite. The medium is reextracted with dichloromethane and the organic phases are washed with brine. After evaporating, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 50/50) to give 3.2 g (100%) of methyl 3-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a colorless honey; 1H NMR (300 MHz, CDCl3): 7.88 (d, J=2.4 Hz, 1H), 7.81 (dd, J=2.4 Hz and 8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.37 (d, J=12 Hz, 1H), 5.88 (d, J=12 Hz, 1H), 4.24 (dd, J=1.2 Hz and 11.7 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 3.87 (s, 3H), 3.69 and 3.60 (2d, J=11.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19](Cl)=[O:20]>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:17]=[CH:18][C:19]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:2]([F:3])([F:4])[F:1])=[CH:7][CH:8]=1)=[O:20]
Reactant: O=C(Cl)C=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: C1COCCO1
Product: O=C(C=Cc1ccc(Cl)c(Cl)c1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
p-Aminophenyl trifluoromethyl ether (0.7 g) pyridine (30 ml) and 3,4-dichlorocinnamoyl chloride (1 g) in dioxane (5 ml) were agitated and heated 3 hours at 80°-90° in a suitable flask fitted with a reflux condenser. The reaction mixture was then poured into 2 l. of ice-water containing conc. hydrochloric acid (50 ml). The crude product was filtered, washed with water and dried. It was recrystallized first from a blend of toluene (50 ml) and hexane (60 ml) and then from toluene (16 ml) and hexane (60 ml).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17]3[N:18]=[C:19](I)[C:20]4[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CN(C=O)C.[Pd]>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(I)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)ncc21

Procedure:
230 mg (0.454 mmol) of 2-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were dissolved in 8 ml of absolute DMF, 150 mg of 10% palladium on carbon were added and the mixture was hydrogenated with hydrogen at standard pressure for 3 h. The reaction mixture was filtered through Celite and concentrated. The residue was triturated with 4 ml of acetonitrile, filtered off with suction and dried under high vacuum. This gave 123 mg of the target compound (purity 94%, 67% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18]Cl)[CH:12]=2)[CH:3]=1.[CH3:20][NH2:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18][NH:21][CH3:20])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(F)c(CCl)c1
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CNCc1cc(Oc2cc(Cl)ccc2C#N)ccc1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 104.6 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-4-fluorophenoxy)-benzonitrile (0.14 g, 0.47 mmol) in ethanol (15 mL) was added methylamine (33% in ethanol, 4.0 mL, 32 mmol), and the reaction mixture stirred for 10 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (50 mg, 0.43 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(4-fluoro-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (183 mg, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[Br:17]Br.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(=O)C>[Br:17][C:9]1[S:8][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Clc1ncc2c(-c3ccccc3)csc2n1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(=O)O
Product: Clc1ncc2c(-c3ccccc3)c(Br)sc2n1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
2-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (0.5 g, 2.03 mmol) was stirred in acetic acid (10 mL). Bromine (0.65 g, 0.21 mL, 4.06 mmol) was added dropwise and the reaction allowed to stir at room temperature over the weekend. The reaction mixture was poured into saturated aqueous ascorbic acid solution. The resulting solid was filtered off and dried in vacuo at 40° C. to afford 6-bromo-2-chloro-5-phenyl-thieno[2,3-d]pyrimidine (567 mg).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CO.[BH4-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1cccnc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccnc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a mixture of 2-bromonicotinaldehyde (50 g, 0.27 mol), methanol (250 mL) and THF (250 mL) in a 3-necked round bottom flask at 0° C. was added sodium borohydride (10.3 g, 0.27 mol) portion wise. The reaction mixture was stirred at 0° C. for 1 hr and warmed up to room temperature. The reaction mixture was adjusted to pH 7 with 2N HCl (120 mL), and concentrated to remove methanol and THF. The resulting mixture was partitioned between EtOAc and brine three times. The organic layer was combined and washed with brine, dried over Na2SO4, and concentrated to give (2-bromopyridin-3-yl)methanol (51 g), which was used without further purification. LRMS (M+H+) m/z 187.9.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:32][C@@H:31]2[C@:18]([CH3:35])([CH2:19][CH:20]=[C:21]3[C@H:30]2[CH2:29][CH2:28][C:27]2[C@:22]3([CH3:34])[CH:23]=[CH:24][C:25](=[O:33])[CH:26]=2)[C@H:3]1[C:4](=[O:17])[CH2:5]OS(C1C=CC(Br)=CC=1)(=O)=O.[CH3:36][C:37]([CH3:58])([CH3:57])[CH2:38][NH:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:43]=[C:42]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)[N:41]=1>>[CH3:36][C:37]([CH3:58])([CH3:57])[CH2:38][NH:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:5][C:4](=[O:17])[C@@H:3]3[C@:18]4([CH3:35])[C@H:31]([C@H:30]5[C:21](=[CH:20][CH2:19]4)[C@:22]4([CH3:34])[C:27](=[CH:26][C:25](=[O:33])[CH:24]=[CH:23]4)[CH2:28][CH2:29]5)[CH2:32][C@H:2]3[CH3:1])[CH2:48][CH2:47]2)[CH:43]=[C:42]([N:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)[N:41]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)CNc1nc(N2CCCC2)cc(N2CCNCC2)n1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(NCC(C)(C)C)n2)CC1
Yield: 74.1 %

Procedure:
16α-Methyl-21-(4-bromobenzenesulfonyloxy)-pregna-1,4,9(11)-triene-3,20-dione is reacted with 2-(2,2-dimethylpropylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine as described in Example 13 to obtain the title compound in a yield of 74.1%, m.p.:130° C.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH:7]([NH2:17])[CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])C.Cl>C1COCC1>[F:10][C:9]([F:11])([F:12])[CH:8]([C:13]([F:14])([F:15])[F:16])[CH:7]([NH2:17])[CH2:6][OH:5]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)C(C(F)(F)F)C(F)(F)F
Yield: 76.6 %

Procedure:
A solution of lithium borohydride (2M THF, 19.8 mL) was added to a solution of 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (5 g, 19.8 mmol), prepared as described (J. Med Chem. 1981, 24, 1043-1047), in THF (80 mL) at 25° C. and was stirred for 4 h. 2M HCl was added to the reaction mixture very carefully until a pH less than 2. The organic solvent was removed in vacuo and the aqueous layer was neutralized with sat NaHCO3 until pH=7. The aqueous layer was extracted with EtOAc (2×50 mL) and the organic extracts were dried over Na2SO4 and concentrated to provide 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine as a yellow oil (3.2 g, 77% yield). The crude oil was of sufficient purity to utilize in the subsequent reaction.