Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1>CCCCCC.C(#N)C>[N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[CH2:38][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC1Cc2ccc(O)cc2C1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CC1Cc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
A mixture of the phenol (15.16 g, 93.58 mmole) of Step D, powdered anhydrous potassium carbonate (12.93 g, 93.6 mmole), 18-crown-6 (2.47 g, 9.36 mmole) and dry acetonitrile (200 mL) is stirred at room temperature under a nitrogen for 15 minutes. 2-Chloromethylquinoline (free base, freshly prepared from 18.29 g or 102.96 mmole of the hydrochloride salt) is added in one portion and the mixture is placed in an oil bath heated at 65° C. for 11 hours (TLC, dichloromethanemethanol 9:1, UV). The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO4) and evaporated to yield an oil which solidifies upon trituration with hexane (ca. 31 g). The crude product is purified by flash chromatography (on silica Merck-60, absorbed in methylene chloride, eluted with CH2Cl2 -ethyl acetate 90:10 and 85:15) to provide 5.95 g of slightly impure material together with 24.55 g of the pure title compound (pale yellow solid, 84.8%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 18.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (47.9 mg, 0.075 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (104 mg, 0226 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk37) (14.6 mg, 19%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:30]=1[C:31](Cl)=[O:32]>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:29]=3[F:28])[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Reactant: O=C(Cl)c1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3cc(F)ccc3F)cc2s1
Yield: 22 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2,5-difluorobenzoyl chloride in DMF was reacted to give the desired compound 0.019 g (22%). LC/MS 433.0 (M+1); LC retention time 2.94 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:18])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][CH:64]([N:66]1[CH:70]=[CH:69][C:68]([NH2:71])=[N:67]1)[CH3:65]>CN(C=O)C>[CH3:12][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=1)[C:23]([NH:71][C:68]1[CH:69]=[CH:70][N:66]([CH:64]([CH3:65])[CH3:63])[N:67]=1)=[O:25])[CH3:18])([CH3:13])[CH3:10]
Reactant: CC(C)n1ccc(N)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (3.00 g, 7.21 mmol), HATU (3.12 g, 8.21 mmol) and 1-(1-methylethyl)-1H-pyrazol-3-amine (1.13 g, 9.01 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL) and ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:3 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%). 1H NMR δ (CDCl3): 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.24 (d, 3H), 1.49 (s, 3H), 1.51 (s, 3H), 3.64 (dd, 1H), 3.78 (dd, 1H), 4.39 (m, 1H), 4.46 (m, 1H), 5.09 (s, 2H), 6.70 (s, 1H), 6.78 (s, 1H), 7.02 (s, 1H), 7.08 (s, 1H), 7.35 (m, 6H), 8.32 (br. s, 1H); m/z 524 (M+H)+, 522 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH2:39][CH2:40][CH3:41])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH2:12][NH:13][CH2:14][C:15]2([NH:20]C(=O)OC(C)(C)C)[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:20][C:15]1([CH2:14][NH:13][CH2:12][C@H:11]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:39][CH2:40][CH3:41])=[CH:6][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCCC(C)COc1ccc([C@H](CNCC2(NC(=O)OC(C)(C)C)CCCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@H](CNCC2(N)CCCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of crude t-butyl 1-(((2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethylamino)methyl)cyclopentylcarbamate from Part A (195 mg, 0.345 mmol) in dichloromethane (2 mL) at 0° C. was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred for 1.5 h while being allowed to warm to room temperature. The mixture was concentrated and the product was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer to afford (2S)-N-((1R)-2-((1-aminocyclopentyl)methylamino)-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (154 mg, 63% yield, 2 steps) as a colorless amorphous solid: 1H NMR (300 MHz, 100° C., DMSO-d6) δ 7.95 (d, J=8.1 Hz, 1H), 7.16-7.34 (m, 5H), 7.11 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 6.87 (br. s., 5H), 4.94-5.06 (m, 1H), 3.68-3.88 (m, 3H), 2.96-3.13 (m, 2H), 2.93 (s, 2H), 1.59-1.95 (m, 9H), 1.40 (d, J=7.0 Hz, 3H), 1.17-1.49 (m, 4H), 0.97 (d, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H); HPLC tR=2.68 min (Method A); LRMS (ESI) m/e 466.5 [(M+H)+, calcd for C29H44N3O2 466.4].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide(0.050 g, 0.152 mmol), morpholine (0.027 mL, 0.305 mmol) and sodium triacetoxyborohydride (0.014 g, 0.228 mmol) in 1,2-dichloroethane (6 mL) was added acetic acid (0.013 mL, 0.228 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h and then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo to give a residue that was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(3-(morpholinomethyl)phenyl)oxazole-4-carboxamide (0.022 g, 0.056 mmol, 37%) as a white solid. 1H NMR (DMSO) δ 2.39 (4H, br m), 3.54 (2H, br m), 3.59 (4H, t), 7.38-7.45 (3H, m), 7.50 (1H, t), 7.71-7.78 (3H, m), 8.13-8.17 (2H, m). LCMS (2) Rt: 2.62 min; m/z (ES+) 400.
Reaction SMILES: [CH:1]([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@H:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1.IC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@@:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)([CH3:1])[CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: [Li]C(C)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@](C)(Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
sec-Butyllithium (1.4 M in cyclohexane, 0.59 ml, 0.824 mmol) was added to a solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one (Example 420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at −78° C. After 15 minutes iodomethane (0.098 ml, 1.57 mmol) was added and the reaction was allowed to warm to room temperature. The reaction contents were poured into saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (10% step gradient elution 30 to 90% EtOAc in hexanes) afforded the title compound as the first eluting diastereomer.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([O:29][CH2:30][CH:31]1[CH2:33][CH:32]1[S:34](Cl)(=[O:36])=[O:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:31]2[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:36])=[O:35])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: O=S(=O)(Cl)C1CC1COCc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCS2
Yield: 844.4 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with 2-benzyloxymethyl-cyclopropanesulfonyl chloride (0.13 g, 0.52 mmol) to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.26 g of the product (86% yield).
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5]C=1.[NH2-].[Li+].[CH3:11][O:12][C:13]([CH3:19])([O:15]CC#C)[CH3:14].BrCC>CCCCCC>[CH3:11][O:12][C:13]([CH3:19])([O:15][CH2:5][C:6]#[C:7][CH2:8][CH3:3])[CH3:14]
Reactant: C=Cc1ccccc1
Reactant: C#CCOC(C)(C)OC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 96.9 %

Procedure:
883 mg (126 mmol) of granulated lithium were added within 5 minutes to 107 g (6.30 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 14.6 g (140 mmol) of styrene were added portion wise within 20 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 9.9 g (70 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (90.8% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 16 hours. 70 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 10.6 g of 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 84.4% (yield 81.8%, based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:27])([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:27])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)CC(C)(N)C(N)=O
Product: CC(C)CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2,4-dimethyl-pentanamide (CAN 113509-60-7) as starting materials, LC-MS (UV peak area/ESI) 100%, 360.2287 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH2:31][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Fc1ccc(C2CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CCC(c2ccc(F)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 34.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-fluoro-2-piperidin-4-ylpyridine (4.7 g, 26.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (4.25 g, 26.5 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.45 g of the intended substance (yield 34.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[Na+]>O>[N:8]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[N+:9]=[N-:10]
Reactant: OCCOCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCOCCO
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A solution of 10.0 grams of 2-(2-chloroethoxy)ethanol in 50 mL of deionized water was treated with 10.4 grams (2 eq) of sodium azide, and the reaction mixture was heated at 80° C. for 48 hours. The solution was cooled to room temperature, saturated with sodium chloride and extracted with 3×50 mL of ether. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to give 7.25 grams (69%) of the desired product as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ=2.05 (t, J=6.4 Hz, 1H, OH), 3.42 (t, J=5 Hz, 2H), 3.63 (dd, J=4.4, 5.6 Hz), 3.71 (dd, J=4.4, 4.8 Hz, 2H), 3.77 (dt, J=4.4, 6 Hz, 2H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1)#[N:19]
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2C#N)CC1
Solvent: O
Solvent: CCCCO
Product: N#Cc1ccccc1O[C@H]1CC[C@H](C(=O)NN)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(2-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.77 mmol) and hydrazine hydrate (0.037 ml, 0.76 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 90%) as white solid, which was used in the next step without further purification. MS m/e: 260 (M+H+)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][S:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 34 (62 mg, 0.14 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated in vacuo. The residue was purified by preparative HPLC to give 35 (58 mg, 76%)as a white solid. MS(ESI): 511 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]#[N:13])=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCC(O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(O)c1ccc(-c2ccccc2C#N)cn1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)propan-1-ol (0.7 g, 3.2 mmol) in toluene (15 mL) and ethanol (8 mL) was added 2-cyano phenyl boronic acid (0.57 g, 3.8 mmol) and a 2M solution of aq. Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.187 g, 0.162 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and the reaction heated to 100° C. for 3 h. The reaction mixture was evaporated under vacuum to remove ethanol, diluted with water (40 mL), extracted with ethyl acetate (200 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 20% ethyl acetate and hexane) to give 2-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile. (0.150 g, 19.4% yield). 1H NMR (400 MHz DMSO-d6): δ 8.67 (s, 1H), 8.02-7.97 (m, 2H), 7.82 (t, 1H), 7.69 (d, 1H), 7.63-7.60 (m, 2H), 1.83-1.68 (m, 2H), 0.89 (t, 3H): LC-MS m/z calcd for [M+H]+ 239.11. found 239.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:5]=[CH:4][C:3]1=2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)CCCC2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCCc2cc(OCC(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A mixture of tert-butyl [(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]acetate (2.8 g, 9.6 mmol), trifluoroacetic acid (10.0 ml) and methylene dichloride (20 ml) was stirred for 2 hours at 0° C. After being concentrated under reduced pressure, the crude residue was triturated using hexane and collected by filtration to give 1.45 g of the title compound as a white solid, which was used for further reaction without purification.