Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:18])[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2

Procedure:
10.0 Parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7 -hexahydro-3H-indazol-3-one and 7.3 parts of phosphorous oxychloride were mixed and heated to 130°-150° for six hours. The reaction mixture was dissolved in 100 parts of chloroform. The organic solution containing the product was washed successively with three portions of 25 parts each of 10% sodium hydroxide and then washed with 50 parts water. The chloroform solution was dried with 2-10 parts of anhydrous sodium sulfate and then filtered. The solvent was removed under a reduced pressure on a rotary evaporator. The resulting thick oil was purified by sublimation at 100°-120° at 0.5-1.5 mm. pressure to yield 7.8 parts of white crystalline material with m.p. 88°-89.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:10][CH2:11][N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][CH2:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(CCN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCN)CCN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 42.8 %

Procedure:
To a solution of N-[7-(p-fluorophenyl)-3,6-di(tert-butoxycarbonyl)-3,6-diaza-1-heptyl]phthalimide (14.5 g, 26.7 mmol) in methanol (200 ml) was added hydrazine monohydrate (1.4 ml) and heated under reflux for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added chloroform (200 ml) and washed with aqueous ammonia (150 ml×2). The organic layer was dried over anhydrous potassium carbonate and the solvent was distilled off under reduced pressure. The resulting colorless oily substance was chromatographed using silica gel column to give 4.7 g of the title compound from the fraction from methylene chloride-methanol-aqueous ammonia (90/10/0.5) as a colorless oily substance. Yield=43%.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)c23)C1
Temperature: 120 °C
Reaction time: 36 h

Procedure:
A mixture of tert-butyl 2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate (660 mg, 1.49 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.49 g, 7.44 mmol), and DIEA (1.30 mL, 7.44 mmol) in n-BuOH (6 mL) was stirred at 120° C. for 36 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (0-50% CH3CN/water) to give the separated diastereomers of tert-butyl 2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate in the following yields: diastereomer #1 (70 mg, 7.5%) diastereomer #2 (80 mg, 8.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.79) (0.43 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.13 g, 33%). MS (ISP) 401.3 [(M+H)+]; mp 249.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:4][CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:6][C:7]=1[S:19]([Cl:18])(=[O:21])=[O:20]
Reactant: O=C1OC(c2ccc(Cl)cc2)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: O=C1OC(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A three-liter, 3-neck flask equipped with a condensor and drying tube, magnetic spin-bar, thermometer and temperature controller was charged with 48.9 grams (0.2 mol) of the 3-(4'-chlorophenyl)phthalide of Example 1 and with chlorosulfonic acid (1467 ml--about 22 moles). The resulting dark-purple mixture was stirred and heated at about 70° C. for about 21/2 hours. The mixture was subsequently added, dropwise, over a period of about 21/2 hours, to a stirred ice-water mixture in order to decompose the chlorosulfonic acid. 3 Kg of ice were initially present in the mixture, and an additional 9.5 Kg of ice were added during the dropwise addition. The solid precipitate formed was recovered by filtration, dissolved in dichloromethane (1000 ml), the solution dried over Na2SO4, filtered, diluted with hexane and concentrated by distillation until buff-colored crystalline needles began to appear. The crystalline solid was recovered by filtration, washed with hexane and dried. As a result of these operations, the desired title compound having an m.p. of 158°-159° C. was recovered in a yield of about 84%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C([Mg]Cl)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]([N:17]([O:18][CH3:19])[CH3:16])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of ethyl 2-(tert-butyldimethylsilyloxy)acetate (59, 20.0 g, 91.59 mmol), N,O-dimethylhydroxylamine hydrochloride (18.76 g, 192.3 mmol) and THF (800 mL) cooled to 0° C. was added dropwise via addition funnel isopropylmagnesium chloride (183.2 mL, 366.4 mmol) and the reaction was stirred for 3 h. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane to afford 15.12 g (70.7%) of 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (60).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])(C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:37])=[O:46])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoic acid (345 mg, 0.86 mmol) in methylene chloride (10 mL) are added triethyl amine (0.36 mL, 2.58 mmol), DMAP (5.0 mg), 3-amino-propionic acid tert-butyl ester (468.2 mg, 2.58 mmol) and EDCI (495.6 mg, 2.58 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoylamino)-propionoate (400 mg).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH2:16][OH:17].C(OCC)C>ClCCl>[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH:16]=[O:17]
Reactant: C/C(=C\c1ccc(C)cc1)CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(=C\c1ccc(C)cc1)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
Solid pyridinium chlorochromate (13.2 g, 0.06 mol) was added in one portion to a pre-cooled (−10° C.) solution of (4E)-4-Methyl-5-(4-methylphenyl)-4-penten-1-ol (9.88 g, 0.052 mol) in dry dichloromethane (250 ml) under nitrogen. After 30 minutes, the reaction was warmed up to room temperature. After 1 hour, diethyl ether (700 ml) was added to the reaction. After stirring for 10 minutes, the reaction was filtered through silica gel, rinsing with diethyl ether. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 10:1) followed by bulb-to-bulb distillation (100° C./0.001 mbar). 3.55 g (yield=36%) of the desired product were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C(F)(F)F)[CH:15]=2)=[CH:4][N:3]=1.[F:24]C1C=CC=CC=1C(N)CCN>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([F:24])=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: NCCC(N)c1ccccc1F
Reactant: FC(F)(F)c1cccc(-c2cnc(Cl)nc2-c2ccncc2)c1
Product: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1

Procedure:
2-Chloro-4-(4-pyridyl)-5-(3-trifluoromethylphenyl)-pyrimidine and 1-(2-fluorophenyl)-1,3-propanediamine were reacted according to the General Procedure, Step C (100° C. for 30 min) to give the title compound. MS (m/z): 468.4 (M+H)+; C25H21F4N5 requir. 467.5 (free base).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 11 g of 3-bromotoluene in 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3; v/v) mixture. This gives 14.5 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=O.Cl.[NH2:22][OH:23].CO>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=[N:22][OH:23]
Reactant: Cc1c(C=O)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2cc(Cl)ccc2n1-c1ccc(O)cc1
Yield: 68 %

Procedure:
A mixture of 5-chloro-1-(4-hydroxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.63 g, 2.2 mmol), hydroxylamine hydrochloride (0.30 g, 4.3 mmol), methanol (25 mL) and pyridine (1 mL) was reacted according to the procedure used in Example 4 to afford a white solid (68%): mp 212-213° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.96 (3H, d, J=8.7 Hz), 7.12 (1H, dd, J=2.2 Hz, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 8.03 (1H, d, J=2.1 Hz), 8.40 (1H, s), 9.93 (1H, s), 10.75 (1H, s); MS m/Z (M+H)+ 301/303 (1 Cl). Anal. for C16H13ClN2O2: Calc'd: C, 63.90; H, 4.36 N, 9.31. Found: C, 63.63; H, 4.12; N, 9.17.
Reaction SMILES: [OH-].[Na+].[NH:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]1[NH2:12].[C:13](OC)(=O)[CH2:14][OH:15]>C(O)C>[CH3:11][C:6]1[N:5]2[N:12]=[C:13]([CH2:14][OH:15])[N:3]=[C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: Cc1cc(C)n(N)c(=N)c1
Reactant: COC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)n2nc(CO)nc2c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
To a solution of 0.79 g of sodium hydroxide in ethanol (20 mL) was added 2-imino-4,6-dimethyl-2H-pyridin-1-ylamine (1.7 g, 0.012 mol; obtained by HPLC purification of intermediate 10). After being stirred at 50-60° C. for 1 hour, methyl glycolate (1.4 g, 0.016 mol) was added, and the resulting mixture was stirred at reflux for 6 hours. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) to afford (5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-methanol (0.2 g, 10%); 1H NMR (300 MHz, DMSO-d6): δ7.39 (s, 1H), 6.87 (s, 1H), 5.38 (t, J=6.3 Hz, 1H), 4.59 (d, J=6.3 Hz, 2H), 2.64 (s, 3H), 2.38 (s, 3H). A mixture of this compound (31 mg, 0.175 mmol) and SOCl2 (10 mL) in dry CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. The solvent and excess SOCl2 was evaporated under vacuum to yield the title compound as a crude product, which was used for the preparation of final compounds without purification or characterization.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20]1[O:23][CH:21]1[CH3:22]>C(O)C>[OH:23][CH:21]([CH3:22])[CH2:20][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH:12]=[O:13]
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)Cn1cc(-c2ccccc2)nc1C=O
Temperature: 100 °C

Procedure:
In a closed vessel a slurry of 4-phenyl-1H-imidazole-2-carbaldehyde (200 mg, 1.16 mmol) and sodium carbonate (60 mg, 0.6 mmol) in ethanol (4 mL) was treated with propylene oxide (170 μL, 2.4 mmol) and heated at 100° C. for 3 h. The cooled solution was filtered and the solids washed with DCM. The volatiles were removed in vacuo to yield the crude title compound which was used without further purification (250 mg, 63%). LC-MS: m/z=231.5 (MH+), tR=0.41 min, method A
Reaction SMILES: P(Br)(Br)[Br:2].C(Cl)Cl.[F:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[CH:17](O)[CH3:18]>O>[Br:2][CH:17]([C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[F:8])[CH3:18]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O
Product: CC(Br)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus tribromide (0.275 mL) and anhydrous methylene chloride (12 mL) were combined and the solution cooled over ice water for 15 minutes. The solution was added to a mixture of 1-(2,4,5-trifluorophenyl)ethanol (0.506 g) and methylene chloride (8 mL), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then poured into H2O and extracted into methylene chloride. The organic phase was isolated, dried with magnesium sulfate, filtered and concentrated (without heat) to give the title compound. 1H-NMR (CD3OD, 400 MHz) δ 2.00 (3H, d, J=7.1 Hz), 5.37 (1H, m), 6.92 (1H, m), 7.36 (1H, m).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)([O-:22])=[O:21]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were added 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (195 mg, 0.65 mmol), 4-(trifluoromethyl)-benzylamine (112 mg, 0.65 mmol), acetonitrile (1 mL) and DIPEA (0.34 mL, 1.96 mmol). The mixture was heated to 80° C. for 24 h at which point the reaction was cooled to RT and concentrated to dryness. The resulting residue was washed with water (2×20 mL) and then dissolved in EtOAc, dried over Na2SO4, filtered and then concentrated. The material was used without further purification. MS (ESI): mass calcd. for C24H18F3N3O3, 453.13; m/z found, 454.1[M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:15][C:16]1[C:28]([N:29]=[C:30]=[O:31])=[CH:27][C:19]2[N:20]([CH2:24][C:25]#[CH:26])[C:21](=[O:23])[S:22][C:18]=2[CH:17]=1>CN(C)C=O.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:30](=[O:31])[NH:29][C:28]1[C:16]([F:15])=[CH:17][C:18]2[S:22][C:21](=[O:23])[N:20]([CH2:24][C:25]#[CH:26])[C:19]=2[CH:27]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)sc2cc(F)c(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 18.51 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of dimethylformamide is added dropwise while stirring at 0° C. during 30 minutes to 4.41 g of a 55% sodium hydride dispersion in 100 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours. The reaction mixture is then cooled to -55° C. and treated during 3 minutes while stirring with a solution of 25.10 g of 6-fluoro-5-isocyanato-3-(2-propynyl)-2-benzothiazolinone in 200 ml of dimethylformamide/toluene (1:1). In so doing, the temperature of the reaction mixture rises to -15° C. and the mixture is subsequently stirred at room temperature for one hour. The thus-formed intermediate 5-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-6-fluoro-3-(2-propynyl)-2-benzothiazolinone is not isolated.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:8]([OH:10])=[O:9].[N:11]([O-])=[O:12].[Na+].Cl.C(OCC)(=O)C>O>[N:11]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=N[O-]
Reactant: O=C(O)C1CCCCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1CCCCCC1C(=O)O
Reaction time: 1 h

Procedure:
At 0° C., a solution of 7.80 g (43.4 mmol) of azepan-2-carboxylic acid and 4.10 g (59.5 mmol) of sodium nitrite in 50 ml of water is acidified to pH 3 using HCl (conc.) and then stirred for 1 h. 50 ml of ethyl acetate are added to the reaction mixture, the organic phase is separated off and the aqueous phase is extracted with 2×50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The 1-nitrosoazepan-2-carboxylic acid obtained (6.80 g, 67%) is taken up in 15 ml of acetonitrile without further purification, and 12.4 g (59.2 mmol) of trifluoroacetic anhydride are added dropwise at 0° C. After 2 h of stirring at room temperature, 8.19 g (59.2 mmol) of potassium carbonate are added, and stirring is continued for a further 20 min. 40 ml of ethyl acetate and 20 ml of water are added to the reaction mixture, and the aqueous phase is extracted with 3×40 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 5.50 g (90%) of the desired product; log P(HCOOH): 0.6; 1H-NMR (DMSO-d6): 4.45 (m, 2H), 2.56 (m, 2H), 1.83 (m, 4H), 1.57 (m, 2H)
Reaction SMILES: COC[O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8](C(C)(C1C=CC=CC=1)C)[C:9]2=[O:15].C(Cl)(Cl)Cl>Cl.CO>[OH:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][NH:8][C:9]2=[O:15]
Reactant: COCOc1ccc(I)c2c1CN(C(C)(C)c1ccccc1)C2=O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NCc2c(O)ccc(I)c21
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
4-Methoxymethoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (463 mg, 1.06 mmol) was dissolved in 10% hydrogen chloride-methanol solution (14 mL), and the solution was stirred at 70° C. for 2.5 hours. Then, the solution was added with 10% hydrogen chloride-methanol solution (4.3 mL) and further stirred at 2.5 hours. The reaction mixture was added with chloroform and purified by slurry. The solid was collected by filtration and washed with chloroform/methanol (9/1). The obtained solid was dried under reduced pressure to obtain 4-hydroxy-7-iodoisoindolinone (248 mg, yield 85%).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH:13]C(=O)C.Cl>C(O)C>[ClH:1].[ClH:1].[OH:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH2:13]
Reactant: CC(=O)Nc1cc(N)ccc1OCC(C)O
Agent: Cl
Solvent: CCO
Product: CC(O)COc1ccc(N)cc1N

Procedure:
0.109 mol (28.4 g) of 2-acetylamino-4-aminophenyl β-hydroxypropyl ether monohydrochloride is dissolved, under reflux, in a mixture of 80 ml of ethanol saturated with hydrogen chloride and 25 ml of 36% strength hydrochloric acid. The reaction mixture is heated under reflux for 11/2 hours. On cooling, the expected product precipitates in the form of the dihydrochloride. The product is filtered off, washed with a small amount of absolute alcohol and dried in vacuo at 50° C. It melts with decomposition at between 215° and 220° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:4]1([CH2:3][CH2:2][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: ClCCN1CCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Yield: 54.5 %

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (1.19 g, 8.83 mmol), 4-hydroxybenzaldehyde (1.02 g, 8.33 mmol), and potassium carbonate (2.30 g, 16.7 mmol) in DMF (5 mL) was heated at 60° C. overnight. The reaction mixture was diluted with H2O and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed (50 mL brine), dried over Na2SO4, and concentrated. The crude material was purified on a silica gel column to yield 4-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde (996 mg, 53%). 1H NMR (CDCl3): δ 9.90 (s, 1H), 7.85 (d, 2H), 7.03 (d, 2H), 4.22 (t, 2H), 2.96 (t, 2H), 2.69 (m, 4H), 1.82 (m, 4H).