Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][C:43]1[N:44]=[C:45]([CH:49]([NH2:51])[CH3:50])[S:46][C:47]=1[CH3:48]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][CH:49]([C:45]2[S:46][C:47]([CH3:48])=[C:43]([CH3:42])[N:44]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1nc(C(C)N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)c(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (19 mg, yield 40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:27](=[O:28])[CH2:26][Cl:25])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 2000039125, prep 27)(25 g, 103 mmol) was dissolved in dichloromethane (300 ml) and 4-methylmorpholine (12.5 ml, 113 mmol) was then added. The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) was added dropwise. The reaction was then allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and the filtrate was evaporated to give the title compound as an off white solid (29.6 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([Cl:13])[N:4]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=1[OH:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:30][C:23]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:22]=2[O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1

Procedure:
In a similar manner, 2-methylthio-4,6-dichloro-5-nitropyrimidine, a compound of formula (A), was treated with 2-benzyloxy-5-cyanophenol to yield 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:16]2[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:15]=2)=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(Cl)cc(Oc2cc(F)c(N)cc2F)n1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 4-amino-2,5-difluoro-phenol (3.5 g, 24 mmol), N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.30 g, 24 mmol) and potassium carbonate (3.4 g, 24 mmol) in DMF (100 mL) was stirred at 50° C. under nitrogen overnight. After cooling to room temperature the reaction mixture was suspended in water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (15%-20% ethyl acetate in petroleum ether) to give N-[4-(4-amino-2,5-difluoro-phenoxy)-6-chloro-pyrimidin-2-yl]-acetamide (3.3 g, 44% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.20-7.24 (dd, J=11.2 Hz, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.64 (dd, J=12.0 Hz, J=8.4 Hz, 1H), 5.48 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>ClCCl>[CH3:13][S:14]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 300 mg (1.83 mmol) of 5-nitroindoline in 20 mL of dichloromethane were added 141 μL (2.74 mmol) of methanesulfonyl chloride and 382 μL (2.74 mmol) of triethylamine, and the mixture was stirred for 2 hours at room temperature. 141 μL (2.74 mmol) of methanesulfonyl chloride and 255 μL (1.83 mmol) of triethylamine were further added to the reaction mixture, and the mixture was stirred for 2 hours at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether, then, the precipitates were collected by filtration to give 410 mg (92%) of the title compound.
Reaction SMILES: S(OC[C@H](CC1C=CC=CC=1)[NH:8][C:9]([O:11]CC1C=CC=CC=1)=O)(=O)(=O)C.[Li+].CC([N-:30]C(C)C)C.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOCC>C1COCC1.C(Cl)Cl>[CH2:34]([NH:30][C:9]([NH2:8])=[O:11])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CS(=O)(=O)OC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)NCc1ccccc1
Temperature: -78 °C
Yield: 48 %

Procedure:
Silyl lactam 1 was dissolved in dry THF (6 mL) and cooled to -78° C. To this solution was then added LDA and the reaction was stirred for 30 minutes at -78° C. after which time benzyl bromide was added via syringe. The reaction was stirred at -78° C. until reaction was complete (1.5 hours, TLC (1:9, ether:CH2Cl2) Rf (st mat.)=0.29. Rf(silyl-prod)=0.62. Rf(BzBr)=0.79). The reaction was then quenched at -78° C. with 6 uL water and then TBAF (1M in THF was added and the reaction was warmed to room temperature and stirred for 3 hours (TLC (1:9, ether:CH2Cl2) Rf(prod)=0.28). The reaction was partition betweem H2O/EtOAc and the organic layer was washed with with water and brine, dried (MgSO4) and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10% ether/CH2Cl2) to yield benzyl product 2 (71 mg, 48%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-:23].[Na+].II.C(Cl)Cl>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:23][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCOCCOCCOCCCCCCCCCCCSSCCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
To a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (145 mg, 0.43 mmol) dissolved in 5 mL of THF was added 1 mL of a NaOH solution (0.1 M), followed by iodine (5 crystals). The solution was stirred at room temperature for 24 h and added to 20 mL of CH2Cl2. After the solution was rinsed with H2O (2×5 mL), the organics were dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography (CH2Cl2/MeOH, 20:1, v/v) to afford 78 mg (54%) of 2. 1H NMR 400 MHz (CDCl3) d 3.72-3.52 (br, 24 H), 3.44 (t, J=7.2 Hz, 4 H), 2.66 (t, J=7.0 Hz, 2 H), 2.41 (br s, 2 H), 1.65 (m, 4 H), 1.57 (m, 4 H), 1.41-1.20 (br, 28 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:13][NH:14][CH:15]([CH3:28])[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCOc1cccc(C(CNC(C)C(=O)N(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide (0.410 g, 1.1 mmol; prepared according to Step 3 of Example 1) in dry THF (5 ml) was cooled to −78° C. and LiHMDS (lithium hexamethyldisilazide), 1 M in THF, (1.43 ml, 1.4 mmol) was added dropwise. The mixture was stirred 30 min then a solution of methyl iodide (0.187 g, 1.3 mmol) in dry THF (1 ml) was added dropwise. The mixture was stirred for 2 h allowing the cooling bath to expire. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (15 ml) and washed with water (2×15 ml). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (silica, petroleum ether:EtOAc from 8:2 to 6:4) affording the title compound (0.22 g, 52% yield) as a colourless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[N-:17]=[N+]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[CH2:1]([O:4][C:5]([C:7]1[C:15]2[C:14](=[O:16])[NH:17][CH2:13][CH2:12][CH2:11][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1c[nH]c2c1C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCOC(=O)c1c[nH]c2c1C(=O)NCCC2
Yield: 23.4 %

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid propyl ester (2.0 g) and NaN3 (2.0 g) in 50 mL of trifluoroacetic acid is stirred at 60-80° C. for a period of 3 days during which additional 2.5 g NaN3 of is added on first, second and third day. After diluted with water, the mixture is extracted with Ethyl acetate. The extract is washed with NaHCO3, brine and concentrated under reduced pressure. The residue is subject to a silica gel chromatography eluting with 10% MeOH in CH2Cl2 to give 500 mg of 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acid propyl ester as a foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[NH:22]([C:24](=[O:36])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[NH2:23]>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][C:24]([NH:22][NH2:23])=[O:36])=[CH:32][CH:31]=3)=[N:7][C:6]1=2
Reactant: NNC(=O)CCc1ccc(B(O)O)cc1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: NNC(=O)CCc1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-(3-Hydrazino-3-oxopropyl)benzeneboronic acid using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[F:12][C:10]1[CH:11]=[C:2]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)cc(F)c2c1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-8-fluoro-2-naphthol (0.66 g, 2.74 mmol) with 3-fluoro-4-methoxyphenyl boronic acid (0.56 g, 3.3 mmol) according to method A to yield 0.67 g (85%) of a white solid: mp 138-140° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.17-7.30 (3H, m), 7.60-7.65 (2H, m), 7.71 (1H, dd, J=2.19 Hz), J=13.14 Hz), 7.90 (1H, d, J=8.37 Hz), 7.99 (1H, bs), 10.15 (1H, bs); MS (ESI) m/z285 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1C#N.Cl.[N+](=[CH2:18])=[N-].[C:19](=[O:22])(O)[O-:20].[Na+]>[OH-].[Na+].C(Cl)(Cl)Cl.C(O)=O.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:19]([O:20][CH3:18])=[O:22]
Reactant: N#Cc1cc2c(nc1Cl)CCCCC2
Reactant: C=[N+]=[N-]
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc2c(nc1Cl)CCCCC2
Yield: 86.3 %

Procedure:
2-Chloro-3-cyano-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (1.50 g, 7.26 mmol) was suspended in 5% sodium hydroxide aqueous solution (25.0 ml) and heated under reflux for 3.5 hours. The reaction solution was adjusted to pH 3 to 4 with concentrated hydrochloric acid and 5% hydrochloric acid at 0° C. and extracted with chloroform, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the thus formed crude crystals were washed with ether to obtain crude carboxylic acid. The crude carboxylic acid was dissolved in chloroform (20.0 ml) to which was subsequently added dropwise ether solution of diazomethane at 0° C. until the material crude carboxylic acid disappeared. Formic acid was added dropwise to the reaction solution at 0° C. to effect decomposition of excess diazomethane, the resulting solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with methylene chloride, and then the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain the title compound (1.50 g, 86.3%) as white powder.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/COc1ccccc1C(=O)O
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccccc1OC/C=C(\C)CCC=C(C)C
Yield: 80 %

Procedure:
In a manner identical to Example 15, 2-geranyloxybenzoic acid(1.37 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.53 g(80%) of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccccn1
Yield: 43 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), pyridine-2-sulfonyl chloride Intermediate 18) (163 mg, 0.92 mmol), pyridine (0.12 ml, 1.54 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (100 mg, 43%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)COc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 24 h
Yield: 24.4 %

Procedure:
[4-(6-Benzyloxyhexanoylamino)-phenoxy]-acetic acid methyl ester 57 (24 grms, 62.33 mmol) was dissolved in a mixture of methanol (200 ml) and dimethyl formamide (50 ml) in a pressure vessel. Palladium on carbon (5%, 15 g) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 24 hours. Catalyst was removed by filtration, and the solvents distilled off under vacuum. Crude 58 was purified by column chromatography on silica gel using chloroform as eluant to get pure 58 (4.5 g, 24.4%) as a white powder with an m.p. between 87.5-90.4° C.
Reaction SMILES: O1CCCC1.[Si]([O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:26][C:27](=[O:41])[C:28]4[N:33]([CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)[N:32]=[C:31]([CH3:40])[C:29]=4[N:30]=3)=[C:21]([O:42][CH3:43])[CH:20]=2)[CH2:15]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH:34]1([N:33]2[C:28]3[C:27](=[O:41])[NH:26][C:25]([C:22]4[CH:23]=[CH:24][C:19]([N:16]5[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]5)=[CH:20][C:21]=4[O:42][CH3:43])=[N:30][C:29]=3[C:31]([CH3:40])=[N:32]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1cc(N2CC[C@@H](O[Si](C)(C)C(C)(C)C)C2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CC[C@@H](O)C2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 3 ml tetrahydrofuran solution of 243 mg (0.452 mmol) of the compound obtained in Example 269, 0.54 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution 0.54 mmoml) was added, and the mixture was stirred at room temperature for 2 hours. Then, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1˜20/1) to obtain 191 mg (quant.) of the captioned compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1>CN(C)C=O.O1CCOCC1.C(N(CC)CC)C>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1cnc(N2CCC3(CC2)OCCO3)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (2.39 g) is combined with 2,5-dichloropyrimidine (2.44 g) in N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (6.7 mL) in a glass pressure reaction vessel and heated with stirring at 120° C. for 16 h. After cooling the orange solution is concentrated and partitioned between dichloromethane (100 mL) and water (100 mL). The water layer is extracted with dichloromethane (100 mL). The dichloromethane layers are combined, washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 20): tR=2.24 min; Mass spectrum (APCI): m/z=256 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38].O>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=3)=[CH:8][C:2]=2[CH3:1])=[O:36])=[CH:30][C:29]=1[C:37]([F:38])([F:39])[F:40]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(C)c2)ccn1
Reaction time: 144 h
Yield: 48.9 %

Procedure:
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea as a brown oil (0.11 g, 0.22 mmol): 1H NMR (DMSO-d6) δ 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH3:30])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH2:29][CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CCCNCC
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;