Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=O)=[C:11]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[N:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][N:50]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>O1CCCC1.CN(C)C=O.O.C(OCC)(=O)C>[N:1]1([C:7]([C:9]2[C:24]([C:25]([F:26])([F:28])[F:27])=[CH:23][C:12]([C:13]([NH:55][C:52]3[CH:53]=[CH:54][N:49]=[N:50][CH:51]=3)=[O:15])=[C:11]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccnnc1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 72 h

Procedure:
To a solution of phenylmethyl 4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoate (may be prepared as described in Description 56; 80 mg, 0.16 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (11.51 mg, 0.48 mmol) and water (1 ml). The mixture was heated at 45° C. for one hour, cooled and 2M hydrochloric acid (0.24 ml, 0.48 mmol) was added. The solvent was removed in vacuo to give a residue. The residue was redissolved in N,N-dimethylformamide (4 ml) and diisopropylethylamine (0.06 ml, 0.32 mmol), 4-pyridazinamine (19.80 mg, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (28.3 mg, 0.21 mmol) and EDC (55.3 mg, 0.29 mmol) were added. The mixture was stirred for 72 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer separated and washed further with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 30 mg.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C:18]([OH:20])=O.C(N(CC)CC)C.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[CH2:50]([NH2:54])[CH:51]([CH3:53])[CH3:52]>ClCCl>[CH2:50]([NH:54][C:18](=[O:20])/[CH:17]=[CH:16]/[CH:15]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:1])([F:25])[F:24])[CH:4]=1)[CH:51]([CH3:53])[CH3:52]
Reactant: O=C(O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Reactant: CC(C)CN
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Yield: 49.5 %

Procedure:
The product of step (d) (1 g, 2.8 mmol) was treated with triethylamine (0.66 mL, 4.8 mmol) and phenyl N-phenylphosphoroamidochloridate (1 g, 3.8 mmol) in dry dichloromethane for 30 mins under nitrogen at room temperature. Isobutylamine (0.66 mL, 6.6 mmol) and triethylamine (0.66 mL, 4.8 mmol) were added and after 24 hours the reaction mixture was subjected to standard work-up procedures. The crude product was purified by column chromatography (1:1 hexane:ether, silica) to give 0.57 g (50% of theory) of N-isobutyl 11-(3'trifluoromethylbenzyloxy)-(2E,4E)-undecadienamide. mp 48°-50°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:17][C:18]3[CH:46]=[CH:45][C:21]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]5[CH:29]=[C:30]([CH:32]6[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]6)[S:31][C:24]=45)=[C:20]([F:47])[CH:19]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[F:47][C:20]1[CH:19]=[C:18]([NH:17][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:10])[CH:46]=[CH:45][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[CH:29]=[C:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:31][C:24]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(4-(3-((4-fluorophenyl)carbamoyl)pyridin-2-ylamino)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (60 mg, 0.091 mmol) and TFA (3 mL). After stirring at room temperature for 4 hours, the mixture was concentrated under high vacuum and aqueous 1M Na2CO3 (5 mL) was added with stirring. The mixture was then extracted with EtOAc (10 mL) and the organics were isolated and dried over sodium sulfate, filtered and concentrated to get product (49 mg, 96%) as a yellow solid. LRMS (esi+) 558 m/z (M+1) detected.
Reaction SMILES: O1CCCC1.[NH2:6][CH2:7][C@@H:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=O)[CH2:10][CH2:9]1.B.O1CCCC1>CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[CH2:7][NH2:6])=[CH:14][CH:15]=1
Reactant: NC[C@H]1CCC(=O)N1c1ccc(F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NC[C@H]1CCCN1c1ccc(F)cc1

Procedure:
To a tetrahydrofuran solution (1.0 mL) of (R)-5-(aminomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (50.0 mg, 0.240 mmol) synthesized in Reference Synthesis Example 216, borane-tetrahydrofuran complex (8.5% tetrahydrofuran solution) (0.760 mL, 0.720 mmol) was added and the resultant mixture was stirred at room temperature for 1 hour 30 minutes. Thereafter, the borane-tetrahydrofuran complex (1.0 mL) was further added and the resultant mixture was stirred at 70° C. for 1 day. After completion of the reaction, methanol was added to the reaction solution and the resultant mixture was stirred at 70° C. for 3 hours, followed by concentrating the reaction solution under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
2-Chloro-5-nitropyridine (10.0 g, 63.08 mmol) and 4-benzyloxyphenol (12.6 g, 63.08 mmol) were reacted in analogy to example 30b. Yield: 19.5 g (96%), M+H+: 323.11.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][NH:8][CH2:9]2)=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(Br)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)ccc1OC1CNC1
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve 3-(4-bromo-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2.9 g, 8.10 mmol) in dichloromethane (45 mL) and slowly add trifluoroacetic acid (15 mL). Stir the mixture for one hour and then evaporate. Apply the residue to two 10 g SCX columns with methanol. Wash the columns with methanol, then elute the material using 2N ammonia/methanol. Concentrate to give 2.09 g (88%) of the title compound as a clear oil.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]([CH3:16])[C:4]=1[CH2:17][CH3:18].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]([CH3:16])[C:4]([CH2:17][CH3:18])=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCc1c(Cl)cc(-c2cccc(Cl)c2)nc1C
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cl
Product: CCc1c(Nc2ccc(CC(=O)OC)cc2)cc(-c2cccc(Cl)c2)nc1C
Temperature: 150 °C
Yield: 40.5 %

Procedure:
An 18-mL test tube was charged with 4-Chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine HCl salt (15 mg, 0.05 mmol, 1 eq.) and methyl 2-(4-aminophenyl)acetate (20 mg, 0.12 mmol, 2.4 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane/ethyl acetate (9:1 then 3:1) as eluent to methyl 2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate (8 mg, 41% yield).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=12.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].C(OCC)(=O)C>[Cl-].[Na+].O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7]/[C:6](=[N:17]\[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[C:5]=12
Reactant: O=C1CCCn2cncc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C1\CCCn2cncc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 1 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridine-8-one [426219-51-4] and 1.2 mmol of 2-methyl-propan-2-sulphinic acid amid is treated dropwise with 0.35 ml of titanium-tetra-isopropoxide. The reaction mixture is stirred at room temperature for 36 hours, then poured into 5 ml of brine and 10 ml of ethyl acetate and stirred vigorously for 10 minutes. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[F:15])=[C:4]([F:18])[CH:3]=1>N.[Ni]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][C:8]=2[F:15])=[C:4]([F:18])[CH:3]=1
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2F)c(F)c1
Agent: [Ni]
Agent: N
Product: NCc1ccc(Oc2ccc(Cl)cc2F)c(F)c1
Yield: 99 %

Procedure:
1.0 g (3.76 mmol) of 4-(4-chloro-2-fluoro-phenoxy)-3-fluoro-benzonitrile were hydrogenated in 30 mL methanolic ammonia solution with the addition of Raney nickel at 50° C. under a hydrogen pressure of 50 psi. Then the catalyst was filtered off and the filtrate was evaporated to dryness. The crude product thus obtained was reacted further without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: COC(=O)CCCCBr
Product: COC(=O)CCCCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 75.2 %

Procedure:
In the same manner as described in Example 38, 050 g (1.171 mmol) of the product of Example 37 and 0.419 mL (2.927 mmol) of methyl 5-bromovalerate provided 0.477 g (75%) of the desired product as a white solid. Electrospray Mass Spec: 542.3 (M+H)+
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:6][CH2:7][CH2:8][O:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[C:16]([OH:18])=[O:17])=[O:11])([O-:3])=[O:2].[CH2:40](I)[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([O:4][CH:5]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:6][CH2:7][CH2:8][O:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[C:16]([O:18][CH2:40][CH3:41])=[O:17])=[O:11])([O-:3])=[O:2]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g (2Z)-4-[({[4,5-bis(nitrooxy)pentyl]oxy}carbonyl)oxy]-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of DMF at RT was added 3 mL of ethyl iodide and 485 mg of potassium carbonate under nitrogen. The reaction was stirred for 30 min, and then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with water (3×), brine and dried over sodium sulfate. Purification by flash chromatography afforded 1.42 g of the titled compound as a colorless oil. 1H NMR (acetone-d6, 500 MHz): δ 7.78 (d, 2H), 7.45 (d, 2H), 7.17 (t, 3H), 7.09 (d, 2H), 5.52 (d, 1H), 5.26 (s, 2H), 5.00 (dd, 1H), 4.73 (dd, 1H), 4.28 (q, 2H), 4.16-4.12 (m, 2H), 3.06 (s, 3H), 1.88-1.79 (m, 4H), 1.27 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[NH2:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:5])[CH3:2]
Reactant: NCC(O)CN1CCOCC1
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCNCC(O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 45 °C
Yield: 45.6 %

Procedure:
5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and 1-amino-3-morpholin-4-yl-propan-2-ol 53c (0.93 g, 5.8 mmol) was added to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight and heated for 14 hours at 45° C. in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with saturated brine (15 ml), exacted with dichloromethane (20 ml×3). The combined organic extracts were concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (600 mg, yield 72.5%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2cc(Cl)c(F)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of ethyl 7-chloro-6-fluoro-4-hydroxyquinoline-3-carboxylate (67 g), sodium hydroxide (12 g), water (350 ml) and industrial methylated spirit (175 ml) was boiled under reflux for 65 hours. The mixture was cooled to ambient temperature and acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and dried to give the novel compound 7-chloro-6-fluoro-4-hydroxyquinoline-3-carboxylic acid, m.p. 263°-265° (dec).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:38][CH2:39][OH:40]>CN(C=O)C.O>[OH:40][CH2:39][CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CN)cc(C(F)(F)F)c2)CC3)ccn1
Reactant: OCCBr
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNCCO)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[7-({[3-(aminomethyl)-5-(trifluoromethyl)phenyl]amino}-carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.459 g, 0.921 mmol) in DMF (10 mL) was added 2-bromoethanol (0.100 mL, 1.41 mmol) and TEA (0.300 mL, 2.15 mmol). The reaction mixture was allowed to stir at rt overnight, and then diluted with water. The mixture was extracted with EtOAc and the combined organic solutions were washed with 10% aqueous LiCl, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 4-{[7-({[3-{[(2-hydroxyethyl)amino]methyl}-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide I-276 (0.352 g, 71%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.65 (s, 1H), 9.19-9.09 (br s, 1H), 8.85-8.77 (m, 1H), 8.50 (d, 1H), 8.17-8.02 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.04-6.94 (m, 2H), 4.22 (t, 2H), 3.83-3.76 (m, 2H), 3.67 (t, 2H), 3.03-2.81 (m, 5H), 2.77 (d, 3H), 2.17-2.08 (m, 1H), and 1.89-1.75 (m, 1H). LCMS: (FA) ES+543.2, ES−541.2.
Reaction SMILES: Cl.Cl.CN1C2CCC1CNC2.C(N=C=O)C.[CH2:17]([N:19](CC)[C:20]([N:22]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([NH:19][C:20]([N:22]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCN(CC)C(=O)N1CC2CCC(C1)N2C
Agent: CCN=C=O
Agent: CN1C2CCC1CNC2
Agent: Cl
Product: CCNC(=O)N1CC2CCC(C1)N2C
Yield: 79 %

Procedure:
8-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (2.5 g, 0.0126 mole), prepared as described in Example 1, was reacted with 2.0 ml (0.0253 mole) ethyl isocyanate according to the procedure described above for 3-(N,N-diethylcarbamyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane in Example 1. A white monohydrochloride, melting point 246°-250° C (dec.) was obtained in 79% yield: 2.33 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[N:12]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>N>[NH2:12][C:3]1[C:4](=[O:11])[NH:5][C:6](=[O:10])[N:7]([CH2:8][CH3:9])[C:2]=1[NH2:1]
Reactant: CCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-amino-1-ethyl-5-nitroso-1,3-dihydropyrimidine-2,4-dione (3.9 g, 21.2 mmol) in 14.5% aqueous ammonia (50 ml) at 50° C. was added sodium dithionite (Na2S2O4, 7.37 g, 42.4 mmol) in portions over 15 minutes, and the mixture was stirred for 20 minutes. The solution was concentrated under reduced pressure to a volume of 30 ml, cooled to 5° C., the precipitate filtered off, and washed with cold water, to provide 5,6-diamino-1-ethyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (15).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:11]Br>CC(O)=O.O>[Br:11][C:2]1[S:1][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1NCCc2ccsc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCCc2cc(Br)sc21
Temperature: 0 °C
Yield: 85.1 %

Procedure:
Dissolve 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (4.80 g, 31.37 mmol) in HOAc (40 mL) and water (30 mL). Cool to 0° C. and add Br2 (1.8 mL, 34.51 mmol) dropwise. Stir the reaction at 0° C. for 1 h. Dilute the reaction mixture with water (100 mL) and extract with EtOAc (3×100 mL). Wash the combined organic layers with 5% Na2SO3 (2×50 mL), saturated NaHCO3 (2×100 mL), dry over Na2SO4, filter, and concentrate to give 6.198 g (85%) of the title compound. MS/ES m/z (81Br) 233.9 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 2.87 (t, J=6.9 Hz, 2H), 3.59 (t, J=6.9 Hz, 2H), 6.21 (bs, 1H), 6.93 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([Cl:25])[CH:17]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:22])=[C:18]([Cl:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nccc(-c2ccc(C(=O)N3CCC(N4CCOCC4)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.27 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoic acid (A-40) using 68 mg (0.40 mmoL) 4-piperidin-4-yl morpholine, 102 mg (0.53 mmol) EDC, 72 mg (0.53 mmol) HOBt and 68 mg (0.53 mmol) DIPEA in 1.2 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 73 mg (51%).
Reaction SMILES: [F:1][C:2]([CH:4]([OH:18])[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:8])[CH3:7])=[CH2:3].[CH2:19]([Zn]CC)C.ICI.O>C(OCC)(=O)C>[F:1][C:2]1([CH:4]([OH:18])[CH2:5][C:6]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])([CH3:8])[CH3:7])[CH2:19][CH2:3]1
Reactant: CC[Zn]CC
Reactant: C=C(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Solvent: ICI
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)C1(F)CC1
Reaction time: 0.08 h

Procedure:
To 2-fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methylhex-1-en-3-ol, stirred under nitrogen gas and cooled on ice, was added 8.0 mL of diethyl zinc (1.1 M in toluene). After 5 minutes, 1.0 mL of diiodomethane was added dropwise over 20 minutes, and the mixture was stirred and allowed to come to room temperature and then stirred at room temperature for 2 days. Then 0.5 mL of water was added, followed by ethyl acetate, and the mixture was filtered through diatomaceous earth. The product was concentrated in vacuo and the residue was fractionated over silica gel (hexanes-dichloromethane (1:1) to dichloromethane, gradient) to give 0.8 g of 1-(1-fluorocyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methylbutan-1-ol as an oil which was used without additional purification.