Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CCOC(=O)COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
(dd) In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 61 (c)] with ethyl bromoacetate there was obtained tert-butyl (3RS,4RS)-4-(4-ethoxycarbonylmethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].[C:12](=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][CH:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29]C=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:31]1[CH:32]=[CH:27][C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:29][CH:30]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)ccc1O
Reactant: ClC(OCc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(Br)ccc1OCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an atmosphere replaced with argon, 2-allyl-4-bromophenol (compound 3), potassium carbonate and benzyloxy-benzylchloride (BnBr) were dissolved in dimethylformamide (DMF), and stirred at room temperature for 3 hours. After confirming that the starting materials were disappeared using thin-layer chromatography (TLC) (with a developer of n-hexane:ethyl acetate=4:1), the reaction liquid was subjected to extraction using 20 mL of water and 20 mL of ethyl acetate. The organic phase was washed with 20 mL of water twice, dried using magnesium sulfate, and then subjected to filtration. The filtrate was concentrated under reduced pressure using an evaporator. The resultant residue was subjected to purification using silica gel flash chromatography (silica gel flash c.c.) (with a developer of n-hexane:ethyl acetate×4:1), to thereby obtain 2-allyl-1-(4-benzyloxy-benzyloxy)-4-bromobenzene (compound 4) as light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:3]=1[NH2:16].S1C=CC=C1.[O-2].[Ca+2].[H][H]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]1[C:3]([NH2:16])=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: Nc1c(Cl)ncnc1NCc1ccccn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cncnc1NCc1ccccn1
Yield: 100 %

Procedure:
A mixture of 62.2 parts of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine, 3 parts of a solution of thiophene in methanol 4%, 20 parts of calcium oxide and 400 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 63.5 parts (100%) of N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine as a residue (interm. 15).
Reaction SMILES: C(O[C:5]1([NH:21][O:22][CH3:23])[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([CH3:19])=[CH:15][C:16]=2[CH3:18])[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.[OH-].[Li+].C(OCC)(=[O:28])C>CO>[CH3:23][O:22][NH:21][CH:5]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([CH3:19])=[C:15]([OH:28])[C:16]=2[CH3:18])[O:11][C:7]2([CH2:8][CH2:9][CH2:10]2)[CH2:6]1
Reactant: CONC1(OC(C)=O)CC2(CCC2)Oc2c(C)c(C)cc(C)c21
Reactant: CCOC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CONC1CC2(CCC2)Oc2c(C)c(C)c(O)c(C)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-(methoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl acetate) (80 mg) in methanol (8 mL) was added lithium hydroxide (4%) water solution under nitrogen. The solution was stirred at room temperature for 2 hours. Ethyl acetate was added. The organic layer was washed with ammonium hydrochloride water solution, water and brine. The solution was evaporated and chromatographed (silica gel, hexane-ethyl acetate 2% to 8%) to give 70 mg of 4-(methoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O)([O-])=O>C(OCC)(=O)C.C(O)C.C(Cl)Cl.[Pd]>[CH:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: O=Cc1cccn1Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: c1ccc2c(c1)Cn1cccc1CN2
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and 3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethyl alcohol is hydrogenated over 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is treated with activated carbon and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is dissolved in methylene chloride containing ethyl alcohol. The solution is passed through a pad of silica gel and the pad washed with a 7:1 hexane-ethyl acetate solution to give 16.31 g of the desired product as solid, m.p. 145°-148° C.
Reaction SMILES: [C:1]1([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH2:11]>>[C:1]1([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH2:2]([CH:1]([CH2:6][CH2:5][CH2:4][CH3:7])[CH2:8][OH:11])[CH3:3]
Reactant: O
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCCC(CC)CO

Procedure:
Solvent (500 g; 90% para-cymene/10% 2-ethylhexanol) and water (2000 g) was charged to a 5 L, 3-necked flask fitted with stirrer, thermometer and distillation head. The mixture was heated to reflux, and oil/water fractions were separated into oil and aqueous layers and the layers weighed to determine the oil:water ratio throughout the distillation. The oil composition was determined by gas/liquid chromatography analysis. Results in Table 4 show that the percent composition relative to the para-cymene and 2-ethylhexanol is substantially unchanged with nearly 95% of solvent recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]#[N:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[C:44](Cl)(=[O:46])[CH3:45].C(=O)([O-])[OH:49].[Na+].C(OCC)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]([O:46][CH2:44][CH3:45])=[NH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40](=[O:49])[NH2:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C#N)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Reactant: O=C([O-])O
Reactant: CC(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=N)c1cnc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)c(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(N)=O)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-cyanopyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1.5 g) is dissolved in ethanol (30 ml) and thereto is added acetyl chloride (14 ml) at 0° C. dropwise. After addition dropwise, the mixture is stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution, the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→1:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonimidoylpyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (221 mg), [MS (m/z): 654 [M+H]+], (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carbamoylpyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (404 mg)[MS (m/z): 626 [M+H]+]and (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonylpyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (596 mg)[MS (m/z): 655 [M+H]+].
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1OCC1CC1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC2CC2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H17ClN4O2, 381; Found, 381.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][C@H:12]([OH:13])[C:22]([F:24])([F:23])[F:21])[CH3:10]
Reactant: CC(CC=O)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C[C@H](O)C(F)(F)F)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reaction time: 0.33 h

Procedure:
To a cooled (−78° C.) solution of (R)-N-(2-(2,3-difluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (13.5 g, 44.5 mmol) in THF (300 mL) was added (trifluoromethyl)trimethylsilane (70.7 mL, 445 mmol) via syringe in 5 min (internal temperature was up to −55° C.). After stirring for 20 min, tetrabutylammonium fluoride, 1.0M solution in THF (66.8 mL, 66.8 mmol) was added dropwise via additional funnel (internal temperature −78 to −50° C. during addition). Addition was completed in 20 min. The reaction was stirred at the same temperature for 1 h. LCMS showed the diastereomer ratio was about 2:3 with the major one as the desired product. The reaction was quenched with 1N HCl (45 ml), and then the cool bath was removed. The reaction mixture was allowed to warm to ambient temperature during which water (100 ml) was added. The solution was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was triturated with minimum DCM. The resulted suspension was filtered. The filter cake was rinsed a few times with DCM and dried in air to afford 6.3 g of desired product as an white solid. The filtrate was concentrated and purified by silica gel column (0-70% EtOA/hexane) to afford additional 911 mg of desired product. MS m/z=374.1 [M+H]+. Calculated for C15H20F5NO2S: 373.4
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22]([NH2:32])[CH:21]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:32][C:22]3[CH:21]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:25]=[CH:24][C:23]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH2:13][CH3:14]
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1ccccc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C(F)(F)F)ccc3-c3ccccc3)ccnc2n1
Temperature: 100 °C

Procedure:
The product from Example 2g as a 3.15M solution in ethanol (0.078 mL, 0.24 mmol) was reacted with the product from Example 218b (0.057 g, 0.24 mmol) for 64 h at 100° C. following the procedure from Example 1g. Consumption of starting material required periodic addition of the product from Example 2g (0.103 mL, 0.32 mmol) in all, and continued heating at 100° C. (70 hrs.). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0058 g, 5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.96 (t, J=7.35 Hz, 3H) 1.73-1.92 (m, 2H) 2.90-3.02 (m, 2H) 6.37 (d, J=6.99 Hz, 1H) 7.32 (d, J=7.72 Hz, 3H) 7.48 (dd, J=7.91, 1.65 Hz, 2H) 7.80 (d, J=8.82 Hz, 1H) 7.86 (d, J=8.09 Hz, 1H) 7.94-8.03 (m, 2H) 8.35 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 408.1 (M+H)+; (ESI−) m/z 406.2 (M−H)−.
Reaction SMILES: [CH2:1]([Sn:4](Cl)([CH3:6])[CH3:5])[CH:2]=[CH2:3].C(CC[Mg]I)(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F.[C:31]([CH2:50][CH2:51]I)([C:34]([C:37]([C:40]([C:43]([C:46]([F:49])([F:48])[F:47])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32].[Mg]>>[CH2:1]([Sn:4]([CH3:6])([CH3:5])[CH2:51][CH2:50][C:31]([F:32])([F:33])[C:34]([F:36])([F:35])[C:37]([F:38])([F:39])[C:40]([F:42])([F:41])[C:43]([F:44])([F:45])[C:46]([F:47])([F:48])[F:49])[CH:2]=[CH2:3]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Reactant: C=CC[Sn](C)(C)Cl
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[Mg]I
Agent: [Mg]
Product: C=CC[Sn](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 46.9 %

Procedure:
Freshly prepared allyldimethyltin chloride (2.86 g, 12.7 mmol) was added dropwise to the Grignard reagent of C6F13CH2CH2MgI, which was prepared from C6F13CH2CH2I (6.0 g, 12.7 mmol) and magnesium powder (0.37 g, 15.2 mmol). The reaction mixture was refluxed overnight (16 h) before quenching with 1N HCl. The crude product was purified by vacuum distillation (112° C./water pump) to give pure 2a as a colorless oil (3.20 g, 35%). 1H NMR (CDCl3) δ 5.95-5.86 (m, 1H), 4.85-4.80 (dd, J=16.8, 1.4 Hz, 1H), 4.73-4.69 (dd, J=11.8, 1.8 Hz, 1H), 2.30-2.12 (m, 2H), 1.83 (d, J=8.5 Hz, 2H), 1.00-0.92 (m, 2H), 0.15 (s, JSn-H=26.3 Hz, 6H); 13C NMR (CDCl3) δ 136.8, 121.8-107.2 (m), 27.9 (t), 16.9, −1.8, −12.2; 19F NMR (CDCl3) δ −81.3 (3F), −117.2 (2F), −122.5 (2F), −123.4 (2F), −123.9 (2F), −126.7 (2F); 119Sn NMR (C6D6): δ −1.4; HRMS: calc. 496.9597 (M+-Me), found: 496.9583. IR (thin film): 1626 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.1-0.3 (m, 4 H), 0.97 (bs, 1H), 2.75-3.02 (m, 2 H) 3.26 (s, 4 H), 3.76 (s, 4 H), 6.25 (bd, 1 H), 7.03 (d, J=12.4 Hz, 1 H), 7.24-7.27 (m, 2 H), 7.38-7.41 (m, 1 H), 7.48 (s, 1 H), 7.56-7.59 (m, 3 H), 7.80-7.83 (m, 1 H), 7.98 (d, J=7.3 Hz, 1 H), 8.20 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.[C:39](=O)([O-])[O-:40].[K+].[K+].O>CN(C)C=O>[N:34]1([C:39]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=4[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:32][CH3:33])=[O:40])[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: c1c[nH]cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCC(=O)n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), imidazole (28 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (59 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:39][N:40]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:40][CH3:39])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2nc(C(=O)NC)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 77 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (74c) (223 mg, 0.43 mmol), methylamine hydrochloride (60 mg, 0.89 mmol), WSC hydrochloride (260 mg, 1.36 mmol) and HOBT (60 mg, 0.44 mmol), to obtain 142.5 mg of the title compound as a white solid (77%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH:11]([C@@H:19]([C:23]1[CH:36]=[CH:35][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[N:38]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([C:10]2[C:3]3[C:2](=[C:7]([F:8])[CH:6]=[C:5]([CH3:9])[CH:4]=3)[NH:1][N:38]=2)[C@@H:19]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:35][CH:36]=2)[CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1
Reactant: O=N[O-]
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(C(=O)c1cc(C)cc(F)c1N)c1ccc(Cl)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@H](c1ccc(Cl)cc1)c1n[nH]c2c(F)cc(C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step A (74 mg, 0.14 mmol) was suspended in concentrated HCl (1 mL) then cooled to 0° C. To the stirred suspension was added a solution of NaNO2 (7.5 mg, 0.11 mmol) in water, then the mixture was stirred for 30 minutes. Solid SnCl2 (47 mg, 0.25 mmol) was added, then the mixture was stirred for another 30 minutes. Ice was added, then the mixture was extracted with EtOAc. The organic phase was washed with water then saturated NaCl(aq), dried over Na2SO4, filtered, then concentrated. The residue was purified by reverse phase HPLC eluting with 10-70% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=7.9 Hz, 2H); 7.43 (d, J=8.1 Hz, 2H); 7.31 (d, J=8.2 Hz, 2H); 7.26 obs, 2H); 7.17 (s, 1H); 6.85-6.78 (m, 2H); 4.60 (d, J=11.6 Hz, 1H); 3.76-3.62 (m, 3H); 2.70 (t, J=5.6 Hz, 2H); 2.41 (s, 3H); 1.59-1.43 (m, 2H); 1.07-0.96 (m, 2H); 0.73 (t, J=7.3 Hz, 3H). LC1 2.36 min. (M+H)+ 522.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[N:8]2S(C)(=O)=O)=[CH:4][C:3]=1[F:22].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[NH:8]2)=[CH:4][C:3]=1[F:22]
Reactant: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-chloro-5-fluoro-1-methanesulfonyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol (0.30 g, 0.82 mmol) in methanol (10 mL) was added 4M sodium hydroxide solution (0.4 mL). The reaction was allowed to proceed overnight at room temperature. Complete reaction was not achieved, so additional 1M sodium hydroxide solution (1 mL) was added and the reaction mixture was heated to 50° C. The reaction mixture was kept at 50° C. for two hours then allowed to stir overnight at room temperature. The reaction mixture was concentrated and to the concentrate was added 1N hydrochloric acid solution and water. The mixture was extracted twice with ethyl ether. The extracts were dried over Mg2SO4, filtered, and evaporated to yield a residue.
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5].[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13](Cl)[N:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13]([NH:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5])[N:12]=1
Reactant: CC(C)(C)C(N)CCO
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)C(CCO)Nc1nc(Cl)c(C#N)cc1F
Temperature: 75 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
To a solution of 3-amino-4,4-dimethylpentan-1-ol (2.00 g, 8.64 mmol) in ethanol (20 mL) was added racemic 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (1.65 g, 8.64 mmol) and 5 mL of N,N,-diisopropylethylamine. The solution was stirred at 75° C. for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromatography (methylene chloride), yielding 2.2 g of 2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.02 minutes (M+H) 286.16