Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14]([NH:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:20]1[N:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:21]=1
Reactant: CCOC(=O)c1nccn1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Br)cn1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of NBS (1.548 g, 8.70 mmol) in DMF (15 ml) was added slowly via addition funnel to a solution of ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (2.22 g, 8.70 mmol) in DMF (12 ml) at room temperature. The reaction was stirred at room temperature overnight. To the reaction was added a saturated solution of sodium bicarbonate until the yellow solution became a white suspension. The mixture was concentrated to dryness. The residue was partitioned between EtOAc and water. The organic phase was washed (brine), dried (Na2SO4) and concentrated to give a yellow viscous oil. The crude product was purified via silica gel column (Isco prep: 15-100% ethyl acetate/hexanes) to afford ethyl 4-bromo-1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (1.52 g, 4.55 mmol, 52.3% yield) as a white solid. LCMS (Method B) m/z 334.1 [M+1], Br-pattern; 1H NMR (400 MHz, chloroform-d) δ 7.26 (s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.51 (s, 9H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (80 mg, 0.23 mmol, Step-1 of Example 353) and sodium hydride (60% in oil, 27 mg, 1.13 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl (2-bromoethyl)carbamate (76 mg, 0.34 mmol) at room temperature. Then the mixture was stirred at 70° C. for 3 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (eluting with n-hexane/ethyl acetate=2/1) to give 112 mg (>99% yield) of the title compound as brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[C:15]1([N:21]2[C:25]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][C:25]3([N:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][NH:23][C:24]3=[O:31])[CH2:30][CH2:29]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3ccccc31)CC2
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of 2.3 parts of 1-(3-choropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.31 parts of 1-phenyl-1,3,8-triazaspiro-[4,5]decan-4-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling to room temperature, water is added. The undissolved product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 0.9 parts (22%) of 8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 228° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([CH2:22][CH3:23])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O>CCOCC>[CH3:8][CH:9]([CH2:22][CH3:23])[CH2:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCC(C)Cc1ccccc1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Phenylmagnesium bromide-ether solution was prepared from bromobenzene (64.5g, 0.41m), magnesium turnings (9.85g, 0.41m), and anhydrous ether (500ml). The reagent was cooled and (+)-β-methylbutyl-4-toluenesulfonate (200g, 0.82m) in ether (800ml) was added in drops. When the addition was complete, the reaction mixture was stirred for two hours, refluxed for two hours and left to stand overnight. Aqueous sulfuric acid was added until a clear solution was formed. The layers were separated. The aqueous layer was extracted with ether (3×250ml), and the combined organic layers were washed with sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was steam-distilled. Fractional distillation of the crude product at reduced pressure yielded (+)-β-methylbutylbenzene (38.7g, 64.8%), bp. 74°-77° C at 12 mm pressure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[NH:13][CH2:12][CH:11]=[N:10][C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)N=CCNC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)NCCNC2=O
Reaction time: 16 h

Procedure:
275 mg 8-tert-Butyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one was dissolved in 5 mL methanol. Sodium cyanoborohydride (139 mg, 2 mmol, 2 eq) was added and the reaction was stirred for 16 hours. The reaction was quenched with water, extracted ethyl acetate 3×, washed saturated sodium bicarbonate, brine, and dried over MgSO4. Solvent was removed under vacuum and the residue chromatographed over silica gel eluting with 80% to 100% ethyl acetate in hexanes to give the title compound, 98 mg, (M+H)+=219.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][O:18][C:19](=[O:23])[CH:20](Br)[CH3:21]>CO.CCN(C(C)C)C(C)C>[CH3:17][O:18][C:19](=[O:23])[CH:20]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:21]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)C(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.9 g, 3.9 mmoles) in MeOH (13 mL) and DIPEA (1.5 mL) was treated with 2-bromo-propionic acid methyl ester (0.48 mL, 4.3 mmoles) and stirred overnight at 70° C. The MeOH was removed under reduced pressure and the residue was purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:33])[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CC(=O)N(Cc1ccccc1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(Cc2ccccc2)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(dimethylaminomethyl-carbonyl)-N-benzyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H32N4O4
Reaction SMILES: [I-].C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N+:9]([CH3:14])([CH3:13])[CH2:8]1)=[O:6])C.OS(O)(=O)=O>O>[CH3:13][N+:9]1([CH3:14])[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([O-:6])=[O:4])[CH2:8]1
Reactant: CCOC(=O)C1CCC[N+](C)(C)C1
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: O
Product: C[N+]1(C)CCCC(C(=O)[O-])C1
Yield: 92.2 %

Procedure:
To a solution of 3-(ethoxycarbonyl)-1,1-dimethylpiperidinium iodide (5) (2.2 g, 6.9 mmol) in water (45 mL) was added conc. H2SO4 (1.0 mL). Dowex® (1×8, 200-400 mesh ‘Cl’) (2.0 g) was added to this solution. The resulting mixture was heated to reflux for 18 h. The resin was filtered off and the aqueous solution was concentrated. The resultant brown oil was triturated with isopropanol to form an off-white precipitate. The precipitate was washed with isopropanol until the color became white. The resulting white precipitate was dried under reduced pressure to give 1.0 g, 93% yield of the desired product. Positive mode ESI/MS: m/z=158 (M+H); confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=3[CH3:24])=[O:16])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=2)=[C:4]([CH3:28])[CH:3]=1.Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:20]=[CH:19][C:18]=3[CH3:24])=[O:16])=[C:11]([N+:25]([O-:27])=[O:26])[CH:10]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(O)ccc2C)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCCN3CCOCC3)ccc2C)c([N+](=O)[O-])c1
Temperature: 130 °C

Procedure:
Compound 505 (0.083 g, 0.22 mmol) and N-(2-chloroethyl)morpholine hydrochloride (0.082 g, 0.44 mmol) were suspended in CH3CN (5 mL). K2CO3 (0.17 g, 1.2 mmol) and NaI (0.008 g, 0.05 mmol) were added and the suspension was heated in a microwave oven at 130° C. for 40 minutes. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 2:3→1:0 as the eluent. This afforded the title compound. 1H NMR (CDCl3) δ 7.34 (d, 1H), 7.21 (dd, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 7.05-6.88 (m, 3H), 6.85-6.78 (m, 2H), 6.16 (s, 1H), 4.02 (t, 2H), 3.72 (m, 4H), 2.75 (t, 2H), 2.54 (m, 4H), 2.45 (s, 3H), 2.25 (s, 3H)
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH2:13])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[F:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH2:30][F:31])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:32])[C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH:13][C:17](=[O:18])[C:16]4[C:20]([F:32])=[CH:21][CH:22]=[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH2:30][F:31])(=[O:26])=[O:27])[C:15]=4[F:14])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cnc2[nH]nc(C3CC3)c2c1
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2[nH]nc(C3CC3)c2c1)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
3-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.024 g, 0.138 mmol), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.045 g, 0.151 mmol), EDCI (0.029 g, 0.151 mmol) and HOBt (0.019 g, 0.138 mmol) were dissolved in DMF (0.52 mL) and stirred at room temperature for 16 hours. The reaction mixture was purified by reverse phase HPLC to give N-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(3-fluoropropylsulfonamido)benzamide (0.031 g, 50%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.17 (s, 1H), 11.06 (s, 1H), 9.92 (br s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.60-7.54 (m, 1H), 7.28 (t, 1H), 4.62 (t, 1H), 4.51 (t, 1H), 3.29-3.23 (m, 3H), 2.33-2.26 (m, 1H), 2.19-2.09 (m, 2H), 1.01-0.93 (m, 3H); m/z (ES-MS) 454.2 (100.0%) [M+1].
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][C:4]([OH:6])=O>O>[OH:6][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][C:2](=[O:1])[CH:3]=1
Reactant: O=C(O)CC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: O
Product: O=c1cc(O)c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
A suspension of 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoic acid (3.26 g; 13.0 mmol; 1 eq) in polyphosphoric acid (26.4 g) is allowed to stir for 4 hours at 140° C. The mixture becomes limpid after 1 h30 stirring. After cooling to room temperature, the orange solution is taken-up in water (100 mL) and sonicated for 5 minutes. The resulting fine powder is filtrated and washed with cold water (4×20 mL). The solid is taken up several times in ethanol (3×100 mL) and concentrated to afford the title compound as a dry light orange powder (2.19 g; 9.6 mmol; 74%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]1[CH2:36][CH2:35][NH:34][C@H:33]([CH3:37])[CH2:32]1)=[CH:26][CH:25]=[CH:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([N:31]1[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][CH:8]3[C:13]4[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=4[CH2:11][CH2:10][O:9]3)[C@H:33]([CH3:37])[CH2:32]1)=[CH:26][CH:25]=[CH:24]2
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Reactant: CS(=O)(=O)OCCC1OCCc2cc(C#N)ccc21
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21

Procedure:
Prepared by condensation of 2-(6-cyano-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate with (3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine, as described for Example 1b).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[N:14]=[C:13]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:23])[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl>[Cl:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:14]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CN(C(=O)CN1CCCC1)N=C2Cc1c(Cl)cncc1Cl
Yield: 55.9 %

Procedure:
A solution under N2 and stirring of 2-chloro-1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazin-2-yl]-ethanone (1.3 g, 3.26 mmoles), prepared as described in example 81, in dry CHCl3 (15 ml) at room temperature was added with pyrrolidine (0.82 ml, 9.78 mmoles) and refluxed. After 20 hours the mixture was poured into water/ice, the phases separated, and the organic one washed with water, anhydrified and brought to dryness to give a residue which was crystallised from acetonitrile (40 ml) to give 0.79 g of the title compound (yield: 58%). m.p.: 148-150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 23-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1 l/1) to provide the crude product, 23-b, (9.5 g, 55%).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6][C:7]([F:25])([F:24])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1.[CH3:26]I.O>CN(C)C=O>[CH:3]1([S:6][C:7]([F:24])([F:25])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([O:15][CH3:26])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 60% sodium hydride (75 mg, 1.87 mmol) in N,N-dimethylformamide (50 ml), 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (0.50 g, 1.44 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (270 mg, 1.87 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.31 g, yield: 60%) was obtained as a colorless oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[K+].O>C(O)(=O)C>[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([Br:1])[CH:30]=2)=[CH:21][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Yield: 26.6 %

Procedure:
Bromine (1.47 mL, 28.69 mmol) in acetic acid (50 mL) was added dropwise over a 30 minutes period into a cold (5° C. mixture of 4′-(2-benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol (7.5 g, 19.13 mmol), potassium acetate (18.6 g, 190.13 mmol), and acetic acid (200 mL). After the addition the mixture was poured into water, and extracted with ethyl ether. The organic extracts were washed with aqueous sodium bisulfite and dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc/CH2Cl2 3:1:1) gave 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol as a light yellow solid (2.4 g): mp 54-56° C. MS m/e 477 (M+);
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[C:32]1([CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: OCCC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
2-Piperidin-4-ylethanol (1.12 g; 8.65 mmol) was introduced into dimethylformamide (DMF, 10 ml). Then hydroxybenzotriazole (HOBT, 1.46 g, 9.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 1.83 g; 9.51 mmol) and diphenylacetic acid (2.02 g; 9.51 mmol) were added in this sequence. N,N-diisopropyl-ethylamine (DIEA; 1.67 ml; 9.51 mmol) was then added to the reaction mixture, which was stirred at RT for 16 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in EA, and the organic solution was washed successively with saturated NaHCO3 solution, 2N HCl and saturated NaCl solution. The organic phase was separated off, dried over Na2SO4, filtered and concentrated. The 1-[4-(2-hydroxyethyl)piperidin-1-yl]-2,2-diphenylethanone (2.39 g; 8.11 mmol) obtained in this way was reacted further without further purification.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:7]=1.N[CH:30](C)CO>>[OH:1][CH2:2][CH:3]([NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:7]=1)[CH3:30]
Reactant: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(N)CO
Product: COc1ccc(C(=O)NC(C)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-38 and (±)-2-amino-1-propanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=C(C3C=CC(NC(NC4C=C(C(F)(F)F)C=CC=4F)=O)=CC=3)C([C:47](NCC(F)(F)F)=[O:48])=C(Br)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[C:9]([CH2:12][O:13][CH3:14])=[C:10]([CH:47]=[O:48])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(Br)c(C(=O)NCC(F)(F)F)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O

Procedure:
The procedure used for the preparation of Intermediate AU was used to prepare the title compound by substituting Intermediate AV (N-{4-[4-amino-7-bromo-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea) for Intermediate AT (4-amino-7-bromo-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)-pyrrolo-[2,1-f][1,2,4]triazine-6-carboxamide). The title compound was obtained as isolated and was used without further purification. MS [M+H]+=503; LCMS RT=3.21 min.