Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:10]1=[S:29].[O:30]=[C:31]1[NH:39][C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[N:32]1[CH:40]1[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]1.O>ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:10](=[S:29])[C@H:9]([NH:8][C:46]([N:43]2[CH2:42][CH2:41][CH:40]([N:32]3[C:33]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:39][C:31]3=[O:30])[CH2:45][CH2:44]2)=[O:47])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Triethylamine (100 μL, 0.720 mmol) was added to a solution of the bis hydrochloride salt of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepane-2-thione (90 mg, 0.240 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (74 mg, 0.264 mmol) in dichloromethane (10 mL) and the mixture heated to reflux. After 18 h, the reaction was allowed to cool to ambient temperature, water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (78 mg). MS 583.2 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[S:14])=[CH:8][CH:7]=1)=O.C(I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[S:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1ccc(NC(=S)NCc2ccncc2)cc1)C(F)(F)F
Solvent: CCI
Solvent: CC(C)=O
Solvent: O
Product: CCNc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To 3.54 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-(4-pyridylmethyl)-2-thiourea [prepared by reacting 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea (Example 19, supra.) with trifluoroacetic anhydride (method of Hickinbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. Acetone is stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:17])=[C:6]([CH:13]=[CH:14][C:15]=1[F:16])[O:7][CH2:8][C:9]([O:11]C)=[O:10])=[O:3].[OH-].[Na+]>O.C(O)(C)C>[NH2:1][C:2]([C:4]1[C:5]([F:17])=[C:6]([CH:13]=[CH:14][C:15]=1[F:16])[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:3]
Reactant: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC(=O)O)c1F
Yield: 8 %

Procedure:
Methyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate (7 mmol, 1 equiv.) was added to a solution of NaOH (1 g, 25 mmol, 3.6 equiv.) in water (20 ml) and isopropyl alcohol (5 ml). The mixture was stirred under reflux for 1.5 h, diluted with water (40 ml) and extracted with CH2Cl2 (40 ml). The aqueous phase was acidified to pH 1 with conc. HCl solution. The precipitant solid was filtered and dried in vacuo to give the desired compound (130 mg, 8%), mp 152-153° C. HPLC-MS (method 1): m/z 312 [M−H+2CH3CN]−, Rt=0.91 min.
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:45][C@@H:46]([CH2:51][N:52]1[CH:56]=[N:55][CH:54]=[N:53]1)[C:47]([O:49]C)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:45][CH:46]([CH2:51][N:52]2[CH:56]=[N:55][CH:54]=[N:53]2)[C:47]([OH:49])=[O:48])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cn1cncn1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NC(Cn4cncn4)C(=O)O)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
Prepared using General Procedure 7 and then 4 (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (90 mg, 0.152 mmol) and (S)-methyl 2-amino-3-(1H-1,2,4-triazol-1-yl)propanoate (25.8 mg, 0.152 mmol) in DMF (2.5 mL) was added TEA (52.8 μl, 0.379 mmol) and then cooled to 0° C. To this mixture was added HATU (57.6 mg, 0.152 mmol) and left at room temperature for 2 h. The reaction mixture was quenched by the addition of 0.1 M Citric acid (aq. 15 mL) and the solid precipitated was allowed to slurry for 30 mins. The solid was filtered, washed with water (10 mL), isohexanes (10 mL) and then dried. Then the solid was dissolved in mixture of THF (4 mL) and MeOH (2 mL). To this solution was added 2M aq. NaOH (380 μL, 0.76 mmol) and the mixture was stirred vigorously at room temperature for 1 h. The reaction mixture was diluted with 0.1 M aq. citric acid (20 mL) and stirred for 1 h. The solid formed was filtered and washed with water (10 mL) and isohexanes (10 mL). The crude product was purified by column chromatography (0-20% MeOH in EA) to afford 12 mg (11%) of 2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-(1H-1,2,4-triazol-1-yl)propanoic acid as a white powder. LCMS-ESI (m/z) calculated for C42H49N7O5: 731.9; no m/z observed, tR=9.75 min (Method 10). 1H NMR (400 MHz, DMSO-d6) δ13.21 (s, 1H), 9.20 (s, 2H), 8.70 (d, J=8.1 Hz, 0.5H), 8.60 (dd, J=8.4, 4.6 Hz, 1H), 8.56 (d, J=7.8 Hz, 0.5H), 8.52 (d, J=7.1 Hz, 1H), 8.37-8.34 (m, 2H), 8.01 (d, J=6.9 Hz, 1H), 7.85-7.82 (m, 2H), 7.80-7.78 (m, 2H), 7.56-7.49 (m, 4H), 7.14 (d, J=8.9 Hz, 2H), 4.87-4.74 (m, 2H), 4.71-4.55 (m, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.24-2.97 (m, 2H), 1.82-1.75 (m, 2H), 1.51-1.29 (m, 17H), 0.95-0.91 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[N:5][C:6]([Cl:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].S(=O)(=O)(O)[OH:16]>>[Cl:14][C:4]1[C:3]([C:1]([NH2:2])=[O:16])=[C:8]([C:9]([F:10])([F:12])[F:11])[CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Product: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C

Procedure:
11.3 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine was gradually added to 22.6 ml of concentrated sulfuric acid, and then the mixture was heated and reacted at 100° C. for one hour. After completion of the reaction, the mixture was poured into ice water, whereupon white precipitates formed. The precipitates were collected by filtration, and the filtrate was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a white solid. This solid and the precipitates previously obtained, were put together to obtain 9.2 g of 2,6-dichloro-4-trifluoromethyl-3-pyridine carboxamide.
Reaction SMILES: Cl.[C:2]([O:5]CC)(=[O:4])[CH3:3].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[CH3:13][C@H:12]1[C@H:3]([C:2]([OH:5])=[O:4])[CH2:8][CH:9]=[CH:10][CH2:11]1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CC=CC[C@H]1C(=O)O

Procedure:
To a cold (0° C.) solution of 7 (103.86 g, 0.286 mol), in 4:1 THF/water (500 mL), was added 30% hydrogen peroxide (160 mL, 1.40 mol), followed by lithium hydroxide (27.4 g, 0.652 mol). The resulting mixture was slowly allowed to warm to room temperature and after 4 h the reaction was complete. The solution was cooled (0° C.) and sodium sulfite (202 g, 1.6 mole) was added. The bulk of the THF was removed in vacuo and the resulting mixture (pH 12-13) was extracted with methylene chloride (5×200 mL) to remove the chiral auxiliary. The combined methylene chloride organics were dried (MgSO4) and the volatiles were removed in vacuo to yield 44.0 g (87% yield) of the recovered benzyloxazolidinone auxiliary. The aqueous layer was acidified to pH 1-2 with 12 M HCl and extracted with ethyl acetate (5×300 mL). The combined ethyl acetate extracts were dried (Na2SO4) and the volatiles were removed in vacuo to yield an oil which was purified by flash chromatography to give a solid (20.2 g, 51% overall yield from 6). The methyl ester of 5 was shown to be at 97% ee on a 30 m Chiraldex column. Rf 0.40 (ethyl acetate/hexane 1:1); m.p. 65-66° C.; 1H NMR (300 MHz, CDCl3) δ 10.2-11.8 (b, 1H), 5.61-5.69 (m, 2H). 2.12-2.33 (m, 4H), 1.89-2.00 (m, 1H), 1.67-1.77 (m, 1H), 1.02 (d, J=6.6, 3H); 13C NMR (75 MHz, CDCl3) δ 182.3, 126.3, 124.5, 46.8, 32.9, 30.3, 28.7, 19.7; MS (EI) m/z 140 (M+, 21), 122 ([M-H2O]+, 16), 111 (14), 95 (100), 79 (75), 67 (49); [α]D−99.0° (c=4.89, CHCl3).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C.C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:17]2[C:22]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([S:32]([C:35]([F:38])([F:36])[F:37])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccncc1
Reactant: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cccnc1SCc1ccncc1
Yield: 37 %

Procedure:
4-Pyridinemethanethiol hydrochloride (0.32 g, 2.0 mmol) and potassium carbonate (0.63 g, 4.5 mmol) were added to a solution of 2-chloro-N-(4-trifluoromethylsulfonylphenyl)pyridine-3-carboxamide (0.65 g, 1.8 mmol, Reference compound No. 2-2) in ethanol (10 mL) under a nitrogen atmosphere, then the mixture was stirred at 65° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), then the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 mL) and brine (100 mL), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was purified by silica gel column chromatography to give 0.29 g of the target compound as a white solid. (Yield 37%)
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[CH:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:14][N:13]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)[nH]n1

Procedure:
Benzoyl acetonitrile from part A hereinabove (10.0 g, 68.9 mmole) and hydrazine monohydrate (4.34 mL, 89.6 mmole) were combined in 95% ethanol (90 mL) and refluxed for 1.5 hours. The solvent was evaporated under vacuum and the crystalline subtitled compound, residue was crystallized from chloroform (three crops, 9.49 g, 86%, m.p. 125°-126.5°, lit., m.p. 123°-125°, Taylor, E. C. et al., J. Org. Chem., (1966), 31, page 1818.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Br)[CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16]C(C)=O.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)n1ccc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc2ccn(C(=O)OC)c2c1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-indole-1-carboxylic acid methyl ester (1.12 g, 4.43 mmol), ethyl acetoacetate (1.23 mL, 9.74 mmol), palladium acetate (20 mg, 0.089 mmol), 2-di-tert-butylphosphino-2′-methylbiphenyl (55 mg, 0.177 mmol) and K3PO4 (2.58 g, 12.2 mmol) in toluene (6 mL) was heated at 100° C. under nitrogen overnight. The reaction was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 93:7) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.3; MS (UPLC): 262.2 [M+H]+, 279.2 [M+NH4]+, 284.2 [M+Na]+, 523.3 [M+Na]+, 545.3 [2M+Na]+; tR (HPLC conditions f): 2.11 min.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]3=[N:17][NH:18][C:19](=[O:24])[C:20]4[CH:21]=[CH:22][CH:23]=[C:14]([C:15]=43)[NH:13][CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:14]3[NH:13][CH:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:11]([C:8]4[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=4)[C:16]([C:15]=23)=[N:17][NH:18]1
Reactant: CCOC(OCC)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of 9-(4-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (270 mg, 0.61 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature for 3 hr. The mixture was then adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (140 mg, yield: 69%) as a light yellow solid.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[C:14]([CH:15]=C)=[N:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:4][C:5]1[C:14]([CH:15]=[O:1])=[N:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[O+][O-]
Reactant: C=Cc1nccc(C(=O)OC)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccnc(C=O)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was bubbled through a solution of methyl 3-fluoro-2-vinylisonicotinate (1.4 g, 7.73 mmol, from Step 2) in methylene chloride (100 mL) at −78° C. until the blue color of excess ozone persisted. Nitrogen was bubbled through the solution for 1 minute to purge excess ozone and then triphenylphosphine (3.9 g, 15 mmol) was added and the solution was warmed to room temperature and stirred overnight. The compound was dry loaded onto silica gel. Flash chromatography eluting with 40% ethyl acetate in hexanes afforded product (0.8 g, 57%) as an off-white crystalline solid. 1H NMR (300 MHz, CDCl3): δ 10.27 (s, 1H), 8.73 (d, 1H), 8.01 (dd, 1H), 4.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][F:20])=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: OCc1ccc(Br)cc1
Solvent: ClCCl
Product: FCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-bromobenzylalcohol (561 mg) in methylene chloride (3 mL) was added [bis-(2-methoxyethyl)amino]sulfur trifluoride (590 μL) over a period of 5 minutes under ice-cooling and the mixture was stirred at the same temperature for 1 hours and then stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→95:5) to give 1-bromo-4-fluoromethyl-benzene (340 mg, yield: 60%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].Cl[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH:11]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14]2
Reactant: Fc1ccc2c(c1)CCCC2Cl
Reactant: C1CNCCNC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)CCCC2N1CCCNCC1
Reaction time: 2 h
Yield: 17403.6 %

Procedure:
Under nitrogen atmosphere, a 3-necked 500 ml round-bottomed flask was charged with homopiperazine (20 mg), DMF (130 ml) and potassium iodide (0.35 g). A solution of 7.70 g (41.7 mmol) of 1-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene in 39 ml of DMF was added over a five minute period. The mixture was stirred at 55°-60° C. for two hours and then at ambient temperature overnight. Tlc analysis on silica gel (diethyl ether:hexane 5:95) showed the absence of the starting halide, Rf 0.77. Most of the DMF was then removed in vacuo (35° C., 0.6 torr) using a rotary evaporator. The residue was treated with 300 ml of water and extracted with ethyl acetate which was then dried (MgSO4). Filtration and removal of solvent in vacuo gave a yellow oil which was kugelrohr distilled to give the title compound, (8.63 g), bp (air bath temperature) 155°-166° C. at 0.26 torr, as a viscous yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.86 (t, 1H, ArCHN), 6.78 (dd, 1H), 6.85 (m, 1H), 7.75 (m, 1H). Anal: Calcd. for C15H21FN2: C, 72.55; H, 8.52; N, 11.28. Found: C, 72.05; H, 8.53; N. 10.95. 1-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene was prepared as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCN(CC)CC>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NS(C)(=O)=O)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine by treatment with methylsulfonyl chloride and Et3N in DMF. Gray solid; 1H-NMR (DMSO-d6) δ: 3.31 (s, 3H, CH3), 3.63 (s, 3H, CH3), 7.32 (m, 1H, pyrimidinyl-H), 7.42 (m, 2H, Ph-H), 8.11 (m, 2H, Ph-H), 8.63 (d, 1H, J=5.0 Hz, pyrimidinyl-H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:25][C@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41]2[C:46]([Cl:47])=[CH:45][N:44]=[C:43](Cl)[N:42]=2)(=[O:33])=[O:32])[CH2:27]1)(C)(C)C>>[Cl:47][C:46]1[C:41]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:31]([N:28]2[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]2)(=[O:32])=[O:33])=[N:42][C:43]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:44][CH:45]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(CC(C)(C)O)CC2
Yield: 65 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as a white solid (80 mg, 65%). mp: 204-205° C., MS (ESI+): 617 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 7.97 (m, 2H), 7.53 (m, 2H), 7.25 (m, 1H), 6.65 (s, 1H), 3.60 (br s, 1H), 3.89 (s, 3H), 3.42 (q, 6 Hz, 3H), 3.30 (m, 2H), 2.87-2.72 (m, 8H), 2.48 (s, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.57 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15](=[O:17])=[O:16].Cl>O1CCCC1>[CH3:12][C:7]1([CH3:13])[C:6]2[CH:14]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCCCc2ccc(C(=O)O)cc21

Procedure:
The Grignard compound was prepared under an argon atmosphere from 4.00 g of 2-bromo-6,7,8,9-tetrahydro-9,9--dimethyl-5H-benzocycloheptene, as described in EP-A2-0315071, and 456 mg of Mg shavings in 20 ml of absolute tetrahydrofuran. After carrying out the metallation a vigorous CO2 stream was introduced at -10° C. The mixture was hydrolyzed with dil. HCl, extracted with ether and washed with a small amount of water. The acid was then purified by extraction in lN NaOH, acidification to pH 1 (HCl) and re-extraction in ether. After washing with water, drying over Na2SO4 and evaporating there were obtained 2.64 g of 6,7,8,9--tetrahydro-9,9-dimethyl-5H-benzocycloheptene-2-carboxylic acid as colorless crystals of melting point 155° C.-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCCCCC1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: Nc1ncnn2c(-c3cccc(CNC4CCCCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 56 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cycloheptanone as starting materials, 136 mg (56%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.00 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (s, 2 H), 2.50 (m, 1 H), 1.80-1.30 (m, 12 H); ES-MS m/z 5542.21 [M+H]+, HPLC RT (min) 2.58.