Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:16]2=[O:31].[C:32]1([Li])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:22][C:18]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[C:15](=[CH:14][C:13]([O:12][CH3:11])=[CH:21][CH:20]=2)[C:16](=[O:31])[CH:17]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[OH:31][C:16]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:18](=[O:22])[CH:17]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc(C2C(=O)c3ccc(OC)cc3C2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2C(=O)c3cc(OC)ccc3C2(O)c2ccccc2)cc1
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C2(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium bis(trimethylsilyl) amide (0.6 N, 7.09 mL, 4.25 mmol) was added dropwise into a cold (0° C.) mixture of 5-methoxy-2-(4-methoxyphenyl)-1H-inden-1,3(2H)-dione (1000 mg, 3.54 mmol) and tetrahydrofuran (15 mL). The mixture was allowed to stir for 1.0 h. Phenyl lithium (4.13 mL, 7.44 mmol) was added dropwise into the mixture at 0° C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with 2 N HCl, poured into water, and extracted with ethyl acetate. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (30%-50% ethyl acetate/petroleum ether) gave 3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-3-phenyl-indan-1-one as a light red foam and 3-hydroxy-5-methoxy-2-(4-methoxyphenyl)-3-phenyl-indan-1-one as a light orange solid: mp 68-70; MS m/e 361 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](=O)([O-])[O-].[K+].[K+].S([O:22][CH3:23])(OC)(=O)=O>CC(C)=O>[CH3:11][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:22][CH3:23])=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OC
Temperature: 25 °C
Yield: 189.4 %

Procedure:
To a stirred solution of salicylic acid (50 g, 143 mmol) in acetone (300 mL) was added anhydrous powdered potassium carbonate (80 g, 580 mmol). Dimethyl sulfate (44.25 g, 290 mmol) was added in portions for about 10 min at room temperature. After the addition was complete, the solution was heated to reflux temperature on a water bath and maintained for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (200 mL). The organic layer was washed with distilled water (2×200 mL), dried over anhydrous sodium sulfate, and concentrated to yield the title Methyl 2-methoxy-benzoate (45 g, 80%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1[NH:14][CH:15]=[C:16]([C:21]2[CH:22]=[N:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:17]=1[C:18]([NH2:20])=[O:19]>O1CCCC1.C(OCC)(=O)C>[C:8]([NH:12][C:13]1[NH:14][CH:15]=[C:16]([C:21]2[CH:22]=[N:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:17]=1[C:18]([NH2:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])nc2)c[nH]c1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])nc2)c1C(N)=O
Reaction time: 3 h
Yield: 64.1 %

Procedure:
0.226 cm3 (1.62 mmol) of triethylamine and 0.058 cm3 (0.809 mmol) of acetyl chloride are added, at a temperature close to 20° C. under an argon atmosphere, to a solution of 0.20 g (0.809 mmol) of 2-amino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carboxamide in 40 cm3 of tetrahydrofuran. After stirring for 3 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is diluted in 200 cm3 of ethyl acetate and then washed with 50 cm3 of water and 50 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.15 g of 2-acetylamino-4-(6-nitropyridin-3-yl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 2.11 (s, 3H); 6.90 (broad m, 2H); 6.95 (d, J=3.0 Hz, 1H); 8.13 (dd, J=2.5 and 8.5 Hz, 1H); 8.27 (d, J=8.5 Hz, 1H); 8.65 (d, J=2.5 Hz, 1H); 10.2 (s, 1H); 11.7 (broad m, 1H).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1>>[C:1]1([CH:7]([NH:9][CH2:10][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(NC(=O)CC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(NCCC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 95 %

Procedure:
Compound 4-[(1 -phenylethyl)aminocarbonyl]methyl-1-[(4-fluorophenyl)methyl]piperidine (0.33 g, 0.93 mmol) was reacted with 1M BH3/THF (5.0 ml) to produce a viscous oil, 0.23 g (95% yield)(procedure E). 1H NMR (CD3Cl) δ 7.34-=7.21 (5H, m, Ar—H), 7.01-6.95 (2H, t, J=8.4 Hz, Ar—H), 4.09-4.07 (1H, d, J=6.0 Hz, NH), 3.77-3.71 (1H, q, J=6.3 Hz, PhCHMe), 3.42 (2H, s, p-FPhCH2), 2.82-2.78 (2H, d, J=10.8 Hz; N(CH)2), 2.55-2.37 (2H, m, NCH2), 1.91-1.83 (2H, t, J=11.4 Hz, N(CH)2), 1.59-1.53 (4H, m), 1.44-1.38 (1H, m), 1.36-1.34 (3H, d, J=6.0 Hz, CH3), 1.25-1.14 (2H, m), The free base was converted into its oxalate salt, m.p.=172-173° C. Anal. [C22H29FN2·2(COOH)2] Calculated: C, 59.99; H, 6.39; N, 5.38; Found C, 59.84; H, 6.46; N, 5.29.
Reaction SMILES: Cl.[NH:2]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)[NH2:3].[O:10]([C:17]1[C:22]([CH:23]=O)=[C:21](OC2C=CC=CC=2)[N:20]=[CH:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C1COCC1>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N:2]1[C:21]2=[N:20][CH:19]=[N:18][C:17]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:22]2[CH:23]=[N:3]1
Reactant: O=Cc1c(Oc2ccccc2)ncnc1Oc1ccccc1
Reactant: Cn1ccnc1NN
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
2-Hydrazinyl-1-methyl-1H-imidazole hydrochloride (Intermediate AV2) (305 mg, 2.05 mmol) was added to 4,6-diphenoxypyrimidine-5-carbaldehyde (Intermediate Z2) (600 mg, 2.05 mmol) in THF (15 mL) the resulting solution was stirred at room temperature for 5 minutes. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.8 g, 6.2 mmol) was added and sealed into a microwave tube. The reaction was heated to 120° C. for 10 hours in the microwave reactor and cooled to RT. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash silica chromatography eluting with 0 to 5% MeOH in DCM to afford the product (190 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 3.59 (3H, s), 6.95 (1H, d), 7.11 (1H, d), 7.24-7.20 (2H, m), 7.32-7.26 (1H, m), 7.44 (2H, m), 8.03 (1H, s), 8.59 (1H, s); m/z (ES+) (M+H)+=293; HPLC tR=1.65 min.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=[O:32])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([O:33][CH3:35])=[O:32])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 66.8 %

Procedure:
To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 19, 3 g, 6.03 mmol) and potassium carbonate (3.33 g, 24.12 mmol) in DMF (30 mL) at room temperature was added methyl iodide (0.454 mL, 7.24 mmol). After 1 hour the reaction mixture was diluted with ethyl acetate and washed three times with water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-30% ethyl acetate/hexanes) afforded the desired product (2.060 g, 66.8%) as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([OH:13])(=O)=[O:11])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([Cl:16])(=[O:13])=[O:11])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1sccc1S(=O)(=O)O
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
7.4 g of crude 3-sulphothiophene-2-carboxylic acid methyl ester are dissolved in 50 ml of thionyl chloride and boiled to reflux for 16 hours. The mixture is then evaporated to dryness in vacuo and the remaining bright-yellow oil is brought to crystallisation with petroleum ether. There is obtained 3-chlorosulphonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]([Cl:21])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of the N-phenylsulfonyl proline (1.5 g, 5.8 mmol) in anhydrous dichloromethane (20 mL), were added oxalyl chloride (2.0 M in dichloromethane, 5.9 mL, 11.8 mmol) and a catalytic amount of dimethylformamide. The solution was stirred for 1 hour at room temperature. The reaction mixture was then condensed and diluted with a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (20 ml). The organic layers were dried over magnesium sulfate (MgSO4) and filtered and concentrated under reduced pressure to yield 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (220 mg) as a yellow solid used without any further purification.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:65][C:66]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH2:78])[CH2:74][CH2:73]1)=[O:71])([CH3:68])[CH3:67]>ClCCl.CN(C)C=O>[C:66]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH:78][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:74][CH2:73]1)=[O:71])([CH3:68])([CH3:65])[CH3:67]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A mixture of 0.10 g (0.22 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.090 g of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-250).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCOc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCOc2cc(F)ccc21
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 7-fluoro-2,3-dihydro-4H-chromen-4-one (6.25 g, 37.6 mmol, US 20050038032) in methanol (60 mL) was added sodium borohydride (1.57 g, 41.4 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and evaporated to remove methanol. The residue was quenched with water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 as an eluent) to afford the title compound as a pale gray solid (4.70 g, 74%):
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[C:18]([N:25](CC3C=CC(OC)=CC=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]3[N:20]([CH:22]=[CH:23][N:24]=3)[N:21]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.CC(O)=O.[H][H].C(O)(C(F)(F)F)=O>[Pd].CO>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]3[N:20]([CH:22]=[CH:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(NCc4ccccc4)CC3)nn3ccnc23)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Product: NC1CCN(Cc2cc(Nc3ccccc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
In a Parr bottle was added 6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.030 g, 0.056 mmol) from (1e), MeOH (7 ml), Pd/C (0.030 mg, 0.282 μmol) and AcOH (0.020 ml, 0.349 mmol). Added hydrogen to a pressure of 55 psi and let shake overnight. The suspension was filtered through celite and rinsed with MeOH, concentrated, and then diluted with TFA (1 ml). The mixture was allowed to stir at room temperature for 6 hours, concentrated and diluted with MeOH (2 ml) and purified by HPLC (10-75% MeOH/Water) to provide the title compound (0.009 g, 49.6% yield) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 8.08 (1H, d, J=2.75 Hz), 7.76 (1H, d, J=2.75 Hz), 7.47 (2H, dd, J=7.56, 3.44 Hz), 7.40-7.45 (2H, m), 7.25-7.31 (1H, m), 6.78 (1H, d, J=3.67 Hz), 4.40 (2H, d, J=3.21 Hz), 3.74 (2H, d, J=11.00 Hz), 3.46 (1H, d, J=3.67 Hz), 3.22 (2H, t, J=12.14 Hz), 2.25 (2H, d, J=14.20 Hz), 2.00 (2H, m). LC/MS, m/z 323 (M+1). HPLC Rt, 1.04 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Fc1cccc(C2=CCCN(Cc3ccccc3)C2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1cccc(C2CCCNC2)c1
Yield: 100 %

Procedure:
A mixture of 6.5 parts of 5-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine hydrochloride and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 4.5 parts (100%) of 3-(3-fluorophenyl)-piperidine hydrochloride as a residue (intermediate 93).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[C:10](=O)([O:14]CC)[O:11][CH2:12][CH3:13]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:12]([O:11][C:10](=[O:14])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:13]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CC(=O)C(C)(C)C
Yield: 91 %

Procedure:
325 g of sodium hydride (80% solution in paraffin oil) were suspended in 2500 cc of diethyl carbonate and 500 cc of hexamethyl phosphoric acid triamide, 500 g of pinacolone (92%) were then slowly added dropwise at 45° to 50° C. and, on completion of the addition the reaction mixture was treated as described in 3 above. The yield was 91% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([NH:18][CH3:17])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
A solution of 4,4′-dichlorobenzhydryl chloride (3.22 g, 11.85 mmol) in a 1.85 M solution of methylamine in tetrahydrofuran (40 ml) was heated at 125° C. in a pressure vessel for 24 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sodium carbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 2.12 g (67%) of the title amine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.57 (3H, s, NCH3), 4.85 (1H, s, CH benzhydryl), 7.0-7.53 (8H, m, aromatics). MS (ESI+) (m/z): 266 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](N)=[O:22].S(=O)(=O)(O)[OH:25]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([OH:22])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl

Procedure:
2.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide and 10 g of 63 % sulfuric acid are heated for 1.5 hours at 100° C. and prepared in accordance with example 2. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained: F 179.5°-181°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([Br:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([F:29])[CH:31]=1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: OB(O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(O)c(F)c1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Yield: 0.2 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.16 mol) was treated with (3-fluoro-4-hydroxyphenyl)boronic acid (38 mg, 0.24 mol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.02 mol) and a solution of sodium carbonate (2M, 317 μl, 0.73 mol) according to the method described in Example 3 to give 150 mg of the title compound that was used in the next step without any further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>CN(C=O)C>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)C(=O)CC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-oxoindane-5-carboxylic acid (2.0 g, 11.5 mmol) in DMF (10 mL) is added diisopropylethylamine (8 mL, 46 mmol), HATU (5.5 g, 14.4 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (5.6 g, 13.8 mmol). The reaction is stirred 1 h at room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) gives the title compound. ESI MS m/z 493.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]([OH:20])=O)=[C:13](O)[CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.[O:37]1CCCC1>>[Cl:17][C:16]1[CH:11]=[C:12]([OH:37])[CH:13]=[C:14]([CH:15]=1)[C:18]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:20]
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cccc2[nH]ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(Nc1cccc2[nH]ccc12)c1cc(O)cc(Cl)c1

Procedure:
A mixture of 3.96 g of 4-amino-1H-indole, 75 ml of tetrahydrofuran, 5.16 g of 5-chloro-salicyclic acid and 6.2 g of dicyclohexylcarbodiimide was refluxed for 2 hours and after the addition of another 0.62 g of dicyclohexylcarbodiimide, the mixture was refluxed for one hour, cooled and was filtered. The filtrate was evaporated to dryness under reduced pressure at 50° C. and the residue was taken up in ethyl acetate. The solution was washed with 2N hydrochloric acid, dried and evaporated to dryness under reduced pressure at 50° C. The residue was chromatographed over silica and was eluted with a 9-1 mixture of chloroform-ethyl acetate to obtain 3.9 g of 5-chloro-3-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 248° C.