Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C:6]([OH:8])=O)([CH3:4])[CH3:3].C[N+](CC[CH2:15][C:16]([O-:18])=[O:17])(C)C.[Cl-:19]>>[CH3:1][N+:2]([CH2:5][CH:6]([OH:8])[CH2:15][C:16]([OH:18])=[O:17])([CH3:4])[CH3:3].[Cl-:19]
Reactant: C[N+](C)(C)CC(=O)O
Reactant: C[N+](C)(C)CCCC(=O)[O-]
Agent: [Cl-]
Product: C[N+](C)(C)CC(O)CC(=O)O
Temperature: 4 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A fermentor equipped for continuous culture which contained 1.5 l of a vitamin containing mineral medium (according to Example 1) with 1.5 percent of betaine and 1.0 percent of γ-butyrobetaine-chloride was inoculated with 150 ml of strain 13 (DSM 2903) preculture of the same medium. After 20 hours of aerobic cultivation at 30° C. and pH 7.0, the culture had grown up and the continuous operation was started at a flow rate of 0.1 l/h. The culture solution flowing out of the fermentor was caught in a vessel cooled at 4° C. the cells were removed by centrifugation. According to enzymatic analysis, the supernatant contained 8.8 g of L-carnitine per 1 of culture. This corresponded to a yield of 99.2 percent (proven analytically), calculated on the concentration of the γ-butyrobetaine-chloride used. The solid L-carnitine chloride was isolated from the solution by means of ion chromatography and water separation.
Reaction SMILES: [Br-:1].C(=[N:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)C1C=CC=CC=1.Br>O>[Br-:1].[NH2:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccccc2)cc1
Agent: Br
Agent: [Br-]
Solvent: O
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N)cc1

Procedure:
5.0 g of 1-(benzylideneamino)-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide are suspended in 300 ml of water. The suspension is then treated with 10 ml of 48 percent hydrobromic acid. The suspension is now subjected to a steam distillation until benzaldehyde no longer results. The solution is evaporated. The residue is treated with ethanol and the solvent is removed by distillation. There is obtained 1-amino-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide as an oil.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:12][CH:11]1[C:30](OC)=[O:31])=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].O1CCCC1>O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:12][CH:11]1[CH2:30][OH:31])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
Methanol (6 ml) is added dropwise taking 30 minutes under reflux by heating, while stirring, to a mixture of methyl 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (6.3 g), sodium borohydride (1.64 g) and tetrahydrofuran (80 ml). The reaction mixture is poured into water, followed by extraction with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off. Crystals obtained from the residue are recrystallized from ethyl acetate-ether to afford 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (4.15 g) as colorless crystals, m.p. 119-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:20]([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.CI>O1CCCC1.CCCCCC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[C:2][CH3:20]
Reactant: [Li]CCCC
Agent: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Agent: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Solvent: O
Solvent: CCCCCC
Solvent: CI
Product: CC#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.55 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene (prepared according to Example 3) in 90 ml of absolute tetrahydrofuran was placed at -20° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 11.0 ml of a 1.0N solution of butyl lithium in hexane. The clear yellow mixture was subsequently stirred at -20° C. for a further 30 minutes and then treated in sequence with 10 ml of hexamethylphosphoric acid triamide and 747 μl of methyl iodide. After warming to room temperature, the now dark violet mixture was stirred for a further 4 hours, subsequently poured into 150 ml of water and extracted three times with 150 ml of petroleum ether each time. The organic phases were washed twice with 200 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.01 g) on silica gel with hexane gave in sequence 806 mg (31.7%) of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene, 431 mg (16.3%) of a mixture of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene and 1-(1-propynyl)-4-(trans-4-pentylcyclohexyl)benzene and 601 mg (22.4 %) of 1-(1-propynyl)-4-(trans-4-pentylcyclohexyl)benzene. A recrystallization of the last fraction from 50 ml of methanol yielded 464 mg of 1-(1-propynyl)-4-(trans-4-pentylcyclohexyl)benzene as colourless crystals; m.p. (C-N) 41.6° C., cl.p. (N-I) 64.9° C.; η(22° C.)=23 cp: η(45° C.)=7.7 cp.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O)(=O)C.N#N>CO.[Pd]>[C:3]([OH:18])(=[O:2])[CH3:4].[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)COc1ccc(C#N)cc1C(=O)OC
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(CN)cc1C(=O)OC
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To a solution of methyl-5-cyano-2-(2-methoxy-2-oxoethoxy)benzoate (5 g, 0.02 mol) in methanol (1 L) was added glacial acetic acid (1.1 g, 0.02 mol) and passed N2 for 30 min. To this was added Pd/C (1.5 g, 35%) and hydrogenated under 2.5 Kg of pressure for 24 h. The reaction mixture was filtered and filtrate concentrated under vacuum (temp. 38° C. under N2). To the crude residue was added 100 mL of EtOAc and again removed under vacuum at same temp. The solid was treated with 100 mL EtOAc, stirred for 2 h, filtered and dried to give the title compound as a white powder (2.25 g, 35%). TLC: chloroform/methanol, 9:1, Rf: 0.15
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].ClCCl.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][OH:26])[CH:19]=1>CN(C)C1C=CN=CC=1.CCCCCC.O>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][O:26][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11])[CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cnc(CO)cc1Br
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, imidazole (2.95 g, 43.3 mmol), 4-dimethylaminopyridine (481 mg, 3.94 mmol) and t-butylchlorodimethylsilane (6.53 g, 43.3 mmol) were added to a dichloromethane solution (100 ml) of (4-bromo-5-methylpyridin-2-yl)methanol (7.96 g, 39.4 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (12.4 g, 39.4 mmol, quant.) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Product: COC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A catalytic quantity of concentrated sulphuric add (1.0 ml) was added to a solution of (3-hydroxy)phenylacetic acid (17.38 g, 0.114tool) in methanol (100 ml). The reaction mixture was stirred for 3 hours at room temperature and then concentrated in vacuo. The residue was partitioned between diethyl ether (200 ml) and a saturated aqueous solution of sodium hydrogen carbonate (200 ml). The ether phase was separated and washed with non-saturated sodium hydrogen carbonate solution (200 ml) and saturated brine solution (100 ml). The ether extract was dried over magnesium sulphate. The solvent was evaporated and the residue dried to afford methyl 3-hydroxyphenylacetate as an amber oil (18.61 g, 98%); δH (360 MHz, CDCl3) 3.58 (2H, s, CH2), 3.70 (3H, s, COOCH3), 5.54 (1H, br s, OH), 6.74 (2H, m, ArH), 6.81 (1H, d, J 8 Hz, ArH), 7.17 (1H, t, J 8 Hz, ArH).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]([O:11][CH3:17])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(C2CCCC2)cc1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a solution of 4-bromo-2-cyclopentyl-5-nitro-phenol (310 mg, 1.08 mmol) and Cs2CO3 (529 mg, 1.62 mmol) in DMF (2.0 mL) was added iodomethane (769 mg, 337 μL, 5.42 mmol) dropwise. The reaction was stirred at 50° C. under inert atmosphere for 16 h. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate/hexane) provided 1-bromo-5-cyclopentyl-4-methoxy-2-nitrobenzene as a light yellow oil (288 mg, 89% yield). 1H NMR (400.0 MHz, DMSO-d6) 7.65 (d, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.29-3.21 (m, 1H), 1.99-1.91 (m, 3H), 1.81-1.50 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1ccccc1

Procedure:
To a solution of phenol (3.16 g, 33.6 mmol) in acetonitrile, was added ethyl 4-bromobutyrate (4.8 ml, 33.6 mmol), potassium carbonate (4.64 g, 33.6 mmol) and tetrabutylammonium iodide (370 mg, 1 mmol). The reaction mixture was stirred vigorously and heated to reflux for 2 days before being cooled, filtered, dried (MgSO4) and concentrated in-vacuo to yield 4-phenoxy-butyric acid ethyl ester. 4-Phenoxy-butyric acid ethyl ester was hydrolyzed to its corresponding carboxylic acid using sodium hydroxide mediated hydrolysis to yield 4-phenoxy-butyric acid. To a solution of 4-phenoxy-butyric acid (7.67 g, 29.6 mmol) in anhydrous dichloromethane was added oxalyl chloride (4.4 ml, 50.3 mmol) and one drop of dimethyl formamide and the reaction mixture stirred at room temperature for 30 minutes. Reaction mixture was concentrated in-vacuo and the residue dissolved in 1,2-dichloroethane (90 ml). This solution was added drop wise to a suspension of aluminum trichloride (4.73 g, 35.5 mmol) in 1,2-dichloroethane (50 ml) at 0° C. Reaction mixture was left stirring in ice bath which rose to room temperature overnight. The reaction mixture was poured over conc. hydrochloric acid (30 ml) stirred into 100 g ice, and then stirred for a further 90 minutes until the ice fully melted. The aqueous phase was washed with dichloromethane 3 times, before the organics were combined, dried (Na2SO4) and concentrated in-vacuo. Purification by triturating with diethyl ether gave 3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH:18][CH2:19][CH2:20][C:21]2[N:29]=[C:28]3[C:24]([N:25]=[CH:26][N:27]3[C@H:30]3[C@H:34]([O:35][Si](C(C)(C)C)(C)C)[C@H:33]([O:43][Si](C(C)(C)C)(C)C)[C@@H:32]([CH2:51][O:52][CH3:53])[O:31]3)=[C:23]([NH:54][CH2:55][CH:56]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:22]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH:1]([N:14]1[CH2:15][CH:16]([NH:18][CH2:19][CH2:20][C:21]2[N:29]=[C:28]3[C:24]([N:25]=[CH:26][N:27]3[C@H:30]3[C@H:34]([OH:35])[C@H:33]([OH:43])[C@@H:32]([CH2:51][O:52][CH3:53])[O:31]3)=[C:23]([NH:54][CH2:55][CH:56]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:22]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CN(C(c5ccccc5)c5ccccc5)C4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CN(C(c5ccccc5)c5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Yield: 68.9 %

Procedure:
The title compound was prepared by a similar method to example 38 using 2-{2-[(1-benzhydryl-3-azetidinyl)amino]ethyl}-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-N-(2,2-diphenylethyl)-9H-purin-6-amine (130 mg, 0.14 mmol) (preparation 38) and a 1 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.4 ml, 0.4 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0.5) increasing in polarity to (90:10:1) to give the title compound (70 mg) as a foam. MS: 726 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C@@H:30]([OH:34])[CH2:31][CH2:32][CH3:33])[CH2:14][N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11].C(N(CC)C(C)C)(C)C.[N+:44]([C:47]1[CH:48]=[C:49]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:50](O)=[O:51])([O-:46])=[O:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:34][C@@H:30]([CH2:31][CH2:32][CH3:33])[C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:50](=[O:51])[C:49]1[CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=[C:47]([N+:44]([O-:46])=[O:45])[CH:48]=1)[CH2:14][N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC[C@H](O)[C@H](CN(CC(C)C)C(=O)OCc1ccccc1)NC(=O)CN
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](O)[C@H](CN(CC(C)C)C(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of the TFA salt of benzyl (2S,3S)-2-(2-aminoacetamido)-3-hydroxyhexyl(isobutyl)carbamate in 1:1 CH2Cl2/DMF was charged successively with N,N-diisopropylethylamine (0.139 mL), 3-nitro-5-trifluoromethylbenzoic acid (39 mg), and HATU (90 mg). The reaction was stirred for 14 h at RT before being partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo to afford benzyl (2S,3S)-3-hydroxy-2-(2-(3-nitro-5-(trifluoromethyl)benzamido)acetamido)hexyl(isobutyl)carba mate (94 mg), which was taken onto the next step without further purification. MS found: (M+H)+=597.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[C:18]([CH3:29])=[N:19][O:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:25]3[CH:26]=[CH:27][C:22]([C:21]4[O:20][N:19]=[C:18]([CH3:29])[C:17]=4[CH:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:10][CH:11]=4)[OH:16])=[CH:23][CH:24]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4ccc(OCc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using (4-benzyloxy-phenyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:21]([CH3:29])=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:26]([C:22]3[NH:23][C:24]([CH3:25])=[C:20]([Cl:19])[C:21]=3[CH3:29])=[O:27])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)c(C)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(C)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (Intermediate 75).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH2:9]1[C:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[CH2:25][CH2:26][NH:8]1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A solution of ethyl (2-tert.-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (8.45 g, 23.6 mmol) in ethyl acetate (80 ml) is treated with a solution of 3M HCl in ethyl acetate (39.3 ml). After stirring at room temperature for 3 h, the solvent is removed in vacuo and the residue azeotroped twice with toluene. The crude product is suspended in diethyl ether, filtered off, washed with diethyl ether and dried. Finally, pure title compound is obtained as beige solid (5.49 g) in 79% yield. tR (LC-2) 1.41 min; ESL-MS (positive ion): m/z 259.33 [M+H]+ (calcd 258.32 for C15H18N2O2).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH3:22])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][CH:19]=[CH:18][C:16]3=2)[CH:11]=[N:10]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1>[N:9]1([CH2:8][C@H:7]([OH:6])[CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][CH:19]=[CH:18][C:16]3=2)[CH:11]=[N:10]1
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C=CCO3)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc3c(c21)C=CCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of the product from Example 4, Step B (0.26 g, 0.76 mmol) and tetrabutylammonium fluoride (1 M, 1.52 mmol) in THF (3 mL) was stirred at ambient temperature for 4 h. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (10 mL) and this mixture was extracted with ethyl acetate (3×5 mL). The combined extracts were dried and evaporated to a residue which was purified by chromatography (silica, 10% to 40% ethyl acetate in hexane) to give the alcohol as an oil (0.14 g, 81%): LC/MS (+APCI) m/z 231 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2.[C:13](=[O:20])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[NH2:14].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:16]([O:15][C:13](=[O:20])[NH:14][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: OC[C@H]1Cc2ccc(Br)cc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@@H](CO)C2
Temperature: 110 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
((S)-5-Bromo-indan-2-yl)-methanol (1.45 g, 6.38 mmol) was dissolved in toluene (12 mL) and argon gas bubbled through the solution for 10 minutes. To the stirring mixture was added, in the following order: tert-butyl carbamate (1.25 g, 10.67 mmol), copper(I) iodide (255 mg, 1.33 mmol), K2 CO3 (2.46 g, 17.8 mmol) and finally N,N′-dimethylethylene-1,2-diamine (285 μL, 2.61 mmol). The mixture was mechanically stirred under argon at 110° C. After 18 hours, tlc monitoring of the reaction showed remaining starting material, the following additional reagents were added: tert-butyl carbamate (125 mg, 1.06 mmol), copper(I) iodide (25 mg, 0.13 mmol), potassium carbonate (250 mg, 1.8 mmol) and N,N′-dimethylethylene-1,2-diamine (30 μL, 0.27 mmol). Heating at 110° C. was continued for 2 hours after which the reaction mixture was cooled, solids removed by filtration and the filtrate evaporated, dissolved in a minimum amount of CH2Cl2 and purified by flash chromatography (ethyl ether). A crude product was obtained which was crystallized from 1:1 diethyl ether:hexane to give ((S)-2-Hydroxymethyl-indan-5-yl)-carbamic acid tert-butyl ester (410 mg, 24%) of white crystals. The mother liquor, comprised of a mixture of desired product and starting material was reserved to be reacted again.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.Br[C:14]#[C:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:14]([O:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[N:3][C:2]=2[Cl:1])[C:15]#[C:16][CH3:17]
Reactant: CCC#CBr
Reactant: Oc1cnc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#CCOc1cnc2c(Cl)nccc2c1
Temperature: 50 °C
Yield: 69.1 %

Procedure:
To a solution of 8-chloro-1,7-naphthyridin-3-ol (618 mg, 3.42 mmol) in DMF (11 ml) were added bromobutyne (882 mg, 6.67 mmol), cesium carbonate (3233 mg, 9.92 mmol). The reaction mixture was heated at 50° C. for 0.5 h. It was quenched with water, and light brown precipitate was formed. It was then collected by Buchner funnel to yield 3-(but-2-yn-1-yloxy)-8-chloro-1,7-naphthyridine (550 mg, 74% yield) as light brown solid. MS m/z: 233.1 [M+H].