Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[C:24]([C:17]1[O:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:26])[CH3:25]
Reactant: CON(C)C(C)=O
Reactant: O=C(O)c1ccco1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (27.5 mL, 0.20 mol) in 200 mL of THF at 0° C. was added n-butyllithium (78.5 mL, 0.196 mol; 2.5M in hexanes). The solution was stirred 30 min and was cooled to -78° C. A solution of furoic acid (10.0 g, 0.089 mol) in 100 mL of THF was added and the solution stirred 30 min. To this mixture was added N-methoxy- N-methyl-acetamide (13.8 g, 0.134 mol) in 50 mL of THF. The reaction mixture was warmed to room temperature and stirred 1 h. The mixture was quenched with saturated ammonium chloride solution and the aqueous layer was washed with ether (3×50 mL) to remove impurities. The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and evaporated to yield 11.1 g (81%) of 2-acetyl-fur-5-yl carboxylic acid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([O:38][CH:39]([CH3:41])[CH3:40])=[N:11][CH:12]=[C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[CH:39]([O:38][C:10]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)=[CH:12][N:11]=1)([CH3:41])[CH3:40]
Reactant: CC(C)Oc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cc1S(N)(=O)=O
Yield: 41.2 %

Procedure:
N-(tert-Butyl)-2-isopropoxy-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.175 g, 0.306 mmol) in TFA (30 mL) was stirred at RT for 12 h. TFA was removed under reduced pressure and reaction mixture was diluted with 10% NaHCO3 (50 mL). The reaction mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-99 as described in general methods) to afford 2-isopropoxy-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (65.0 mg, 40.8%) as a white solid. LCMS Condition B-39: retention time 2.32 min, [M+1]=516.2. HPLC Condition B-5: retention time 8.21 min, purity 99.29%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=7.1 Hz, 6H), 4.88 (d, J=4.5 Hz, 2H), 5.14 (quintet, J=6.8 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 7.08 (s, 2H), 7.24-7.31 (m, 2H), 7.42-7.49 (m, 2H), 7.50-7.62 (m, 4H), 7.77 (td, J=7.7 Hz, J=1.8 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H), 8.42 (dt, J=5.1 Hz, J=1.2 Hz, 1H), 8.65 (d, J=2.5 Hz, 1H), 8.73 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:18])(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To cooled (0° C.) solution of 30 (12.0 g; 49.12 mmol) in dichloroethane (200 mL) was added phosphorus pentachloride (20.5 g; 98.24 mmol) slowly and portion-wise. After addition was complete, the reaction was heated at reflux overnight, cooled to room temperature, and then concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 50% v/v over 400 mL gradient elution) to give the title product as a dark solid (8.45 g; 65% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:43])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:42])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 was used as the starting compound and 4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl bromide was used instead of 3,3-diphenyl bromide. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [OH:1][NH:2]Cl.C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16]>O>[OH:1][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: ONCl
Reactant: O=C(O)C(=O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccs1
Yield: 47.9 %

Procedure:
A cooled solution of hydroxylamino hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0°) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the oxime (syn-isomer) (1.05 g; 51%), m.p. 1320,λmax. (ethanol) 284 mm (ε9,500), νmax. (Nujol) 2590 and 1706 (CO2H) and 1655 cm-1 (C=N), (DMSO-d6), -2.5 to -9.5 (broad multiplet; N-OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20](N1CCOCC1)=[O:21]>C1COCC1>[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:21]
Reactant: Brc1cnc2ccccc2c1
Reactant: COC(OC)C(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)c1cnc2ccccc2c1
Reaction time: 0.25 h

Procedure:
3-Bromoquinoline (3.29 ml., 0.032 mol) was dissolved in 300 ml. THF and cooled to -78°. n-Butyllithium (13.6 ml. of 2.5M in hexane, 0.034 ml.) was added slowly and the mixture stirred 15 minutes at -75° to -78°. N-(Dimethoxyacetyl)morpholine (5.98 g., 0.032 mol) in 10 ml. THF was then added and stirring continued for 1.75 hours at the same temperature. The reaction was then quenched into 300 ml. saturated NH4Cl. The aqueous layer was separated and extracted 4×100 ml. ether. The organic layers were combined, dried over MgSO4O, stripped to yield title product, 7.0 g., bp 120°-123°/0.125 torr.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.O.[NH3:12]>>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH2:12])=[N:7]2
Reactant: N
Reactant: Clc1ccc2nccn2n1
Solvent: O
Product: Nc1ccc2nccn2n1
Yield: 67.3 %

Procedure:
A solution of 6-chloroimidazo[1,2-b]pyridazine (5.00 g, 32.6 mmol) in a 25% aqueous ammonia water (50 ml) was stirred in a sealed tube at 180° C. for 8 hours, and the reaction solution was distilled off under reduced pressure. A form solid was separated by filtration, which was washed with water to give 2.94 g (67.3%) of the desired product as a solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH2:6]1)=[N+]=[N-].[C:17]([OH:20])(=S)[CH3:18]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH:1][C:17](=[O:20])[CH3:18])[O:9][N:8]=2)=[N:11][CH:12]=1
Reactant: CC(O)=S
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Product: CC(=O)NCC1CC(c2ccc(Br)cn2)=NO1
Reaction time: 52 h

Procedure:
5-Azidomethyl-3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazole (3 g, 10.6 mmol) and thioacetic acid (10 ml) were combined and stirred for 52 hours. The reaction mixture was concentrated in vacuo and then ethyl acetate (20 ml) was added. The resulting precipitate was filtered and washed with ethyl acetate (2×20 ml) to give the desired product (1.8 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH3:42])[CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.15 mmol) and 1-iodopropane (31 mg, 0.18 mmol) in DMF (2 mL) was added potassium carbonate (37 mg, 0.27 mmol). The reaction was heated (50° C.) for 17 h. The reaction was cooled to rt and was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by trituration with Et2O to obtain 21 mg (25%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.97-7.91 (m, 3 H), 7.81 (d, 1 H), 7.65 (s, 1 H), 7.37-7.26 (m, 5H), 7.19 (d, 1 H), 7.04-6.96 (m, 3 H), 5.66 (s, 2 H), 325-3.15 (m, 4 H), 2.51-2.48 (m, 4 H), 2.32-2.24 (m, 2 H), 1.53-1.42 (m, 2 H), 0.88 (t, 3 H), 2.89 (s, 4 H); ES-MS m/z 543.4 [M+H]+, HPLC RT (min) 2.40.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[F:35][C:36]([F:43])([F:42])[CH2:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:37][C:36]([F:43])([F:42])[F:35])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)CC(F)(F)F
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)CC(F)(F)F)cnn12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.12 g, 0.27 mmol) obtained in Example 39, step 2 and 2,2,2-trifluoroethanesulfonamide (WO1984/02650, 0.21 g, 1.33 mmol), the title compound (0.07 g, 43%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](OCC)=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:14])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1ccco1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccco1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml) was dropwise added lithium bis(trimethylsilyl)amide (100 ml, 100 mmol) over 1 hour at 0° C. under an atmosphere of nitrogen gas, followed by stirring as it was for 2 hours. Hexane (140 ml) was added to the reaction mixture, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous ammonium chloride solution twice and brine, dried over anhydrous sodium sulfate and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:31]1(C)[CH:36]=CC(S(O)(=O)=O)=C[CH:32]=1>C(O)CC>[CH2:32]([O:27][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14]2=[O:21])=[CH:30][CH:29]=1)[CH2:31][CH3:36]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Solvent: CCCO
Product: CCCOC(=O)c1ccc(N2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CC=CC[C@@H]3C2=O)cc1

Procedure:
A solution of 1 g of compound 67 and 1 g of p-toluenesulfonic acid in 100 ml of 1-propanol was refluxed for 18 h. After evaporating the solvent, the title compound was crystallized from methanol. M.p. 100°-101° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1O
Temperature: 60 °C

Procedure:
A mixture of 2,3-dihydroxybenzoic acid (5 g), methanol (50 ml) and concentrated sulphuric acid (10 drops) was stirred and heated to 60° C. for 24 hours. The mixture was evaporated and the residue was taken up in ethyl acetate. The organic solution was washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to give methyl 2,3-dihydroxybenzoate (2.19 g); NMR Spectrum: (CDCl3) 3.95 (s, 3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, H), 7.35 (d, H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.O=S(Cl)[Cl:19]>O1CCOCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[Cl:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1ccccc1-c1ccc(CCl)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a cooled (0° C.), stirred solution of 2-[5-(hydroxymethyl)pyridin-2-yl]benzonitrile (4.3 g, 0.020 mol) and ZnCl2 (0.09 g, 0.61 mmol) in p-dioxane (40 mL) was added SOCl2 (1.50 mL, 0.020 mol) dropwise. The mixture was stirred at room temperature for 18 h, diluted with ether, washed with water and brine, dried (MgSO4), and concentrated to give 4.30 g (92%) of product as a brown solid, mp 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C1C(=O)N([I:19])C(=O)C1.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[C:4]([I:19])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc(I)c1O
Temperature: 60 °C
Reaction time: 20 h

Procedure:
5-Chlorosalicylic acid (20 g, 115.8 mmol) is dissolved in DMF (100 mL). To this solution is added NIS (26.1 g, 116.0 mmol) which causes the reaction to warm up to 60° C. The reaction is stirred at room temperature for 20 hours. At this point ethyl acetate (100 mL) is added and the solution washed with 0.1N HCl (100 mL). The organic phase is then washed with water (3×100 mL), dried with sodium sulfate and evaporated under reduced pressure to yield 5-yield 5-chloro-3-iodosalicylic acid as off-white solid. (mp 160°-163° C.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6]>C(Cl)(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6]
Reactant: Cc1ccc(CO)cc1Br
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C=O)cc1Br
Temperature: 70 °C
Yield: 68.5 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzyl alcohol (4.43 g, 22 mMol) in CHCl3 (100 mL) was added MnO2 (15 g, 172 mMol). The reaction was stirred and refluxed (70° C. oil bath) for 18 h, cooled to RT, filtered through Celite®, rinsed with CHCl3, and concentrated to dryness under vacuum. Purification by flash chromatography on silica gel (10% EtOAc, hexanes) gave the title product (3.0 g, 68%). 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.75 (d, J=1.5 Hz, 1 H), 7.73 (d, J=8.1 Hz, 1 H), 7.57 (dd, J=8.1, 1.5 Hz, 1 H), 7.28 (s, 1 H), 2.50 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.8 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of acetone, and 8.3 g of anhydrous potassium carbonate and 14.2 g of methyl iodide are added thereto. The mixture is stirred at room temperature for 6 days. The reaction mixture is treated in the same manner as described in Preparation 1-(2), whereby 9.0 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.8% The physico-chemical properties of this product are identical with those of the sample obtained in Preparation 1-(2).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:3]1.O[Li].O>O1CCOCC1.O>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:2]([CH3:24])([CH3:1])[CH2:3][C@@H:4]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC1(C)C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a mixture of (R)-2-benzyl 1-tert-butyl 4,4-dimethylpyrrolidine-1,2-dicarboxylate (D40) (198 mg, 0.59 mmol) in dioxan/water (4/4 ml), LiOH.H2O (100 mg, 2.37 mmol) was added and the mixture was left stirring at RT for 18 hrs. Organic solvent was evaporated off and the reaction mixture was diluted with water (8 ml), washed with Et2O (2×10 ml), acidified with acetic acid to pH˜4-5 and extracted with Et2O (3×10 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D41) (84 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:19]I>C(Cl)Cl.C(OCC)C.N([O-])=O.[Ag+]>[F:1][C:2]1[C:3]([C:9]2[C:13]([I:19])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Reactant: II
Agent: [Ag+]
Agent: O=N[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nc(-c2ncc(Cl)cc2F)c(I)c1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
3.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H15) are dissolved in 30 ml of methylene chloride, and 1.83 g of silver(I) nitrite and 3.02 g of iodine are then added. The mixture is stirred overnight at 22° C. It is then diluted with diethyl ether and extracted successively with aqueous sodium metabisulfite solution and brine. After drying of the organic phase over sodium sulfate and filtration, the filtrate is concentrated in vacuo together with twice the amount of silica gel. After application of this silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate (3/1). 3.97 g of the desired title compound are obtained as a beige solid of melting point 77-78° C. in this manner.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1I
Temperature: 25 °C

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 mL) was heated at reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated under reduced pressure to afford 3-iodo-4-methylbenzoyl chloride. A solution of 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloromethane (10 mL) was added slowly to a 0° C. solution of 3-amino-4-fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 mL). The reaction stirred at 0° C. and warmed to room temperature over 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate-hexane) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 MS m/z found 423.9 [MH+]; calc. for C15H10F4INO=423.14.