Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:9](Cl)=[O:10].[N+:12](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-:13].CC1(C)CCCC(C)(C)N1.[Li]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[N+:12]=[N-:13])[C:9]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]=1[Cl:1])=[O:10])[CH3:19]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(Cl)C1=C(Cl)CCCCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C1=C(Cl)CCCCC1
Reaction time: 1 h

Procedure:
To a solution of 2-chlorocyclohept-1-enecarbonyl chloride (4.6 g) and ethyl diazoacetate (2.8 ml) in THF (30 ml) cooled to −70C was added a solution of lithium 2,2,6,6-tetramethylpiperidine (1 equiv.) dropwise. On completion of the addition the reaction mixture was stirred for 1 h. The reaction mixture was quenched by pouring into 1M citric acid (100 ml), then extracted with ether (3×200 ml). The ether extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient elution: hexane/ether (10:1) 500 ml, hexane/ether (9:1) 500 ml, hexane/ether (8:2) 500 ml. The appropriate fractions were combined and evaporated under reduced pressure to give a yellow oil. δH (360 MHz; CDCl3) 1.33 (3H, t, J=7 Hz, CH3), 1.74 (6H, m, CH2), 2.32 (2H, m, CH2), 2.64 (2H, m, CH2), 4.29 (2H, t, J=7 Hz, CH2).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Br:15])(=O)C.Cl>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Br:15]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Agent: Cl
Product: Nc1ccc(CC(=O)O)cc1Br

Procedure:
44.5 g (0.164 mole) of 4-acetamido-3-bromophenylacetic acid and 131 ml of 6 N hydrochloric acid are heated to 100° C. for 2 hours. The solution of 4-amino-3-bromophenylacetic acid (which is thus formed) is cooled to -6° C. in an ice-sodium chloride bath, and a solution of 11.7 g (0.17 mole) of sodium nitrite in 130 ml of water is added dropwise thereto at -6° C. Stirring is continued for a further hour at the same temperature, and the thus-prepared solution of the diazonium salt is poured slowly into a solution (which is cooled to -10° C.) of 100 g (0.443 mole) of tin(II) chloride dihydrate in 100 ml of concentrated hydrochloric acid to form 3-bromo-4-hydraziniumphenylacetic acid chloride. Dilution of the latter with 300 ml of water is effected, and 36 ml (0.163 mole) of 1,1,3,3-tetraethoxypropane are added dropwise thereto; stirring is then effected for 4 hours at room temperature. The resulting reaction mixture is rendered alkaline with 35% strength solution of sodium hydroxide and is heated to 100° C. for one hour in order to hydrolyze 3-bromo-4-(pyrazol-1-yl)phenylacetic acid ethyl ester, which is formed simultaneously along with the corresponding free acid. The produced ethanol is distilled off, and clarification is effected with activated charcoal. This is followed by acidification with hydrochloric acid and extraction with chloroform. The organic phase is dried. Concentration to dryness is effected in a vacuum, and the residue is recrystallized from benzene to obtain 38.5 g (83.5% of theory) of 3-bromo-4-(pyrazol-1-yl)phenylacetic acid (m.p. 100° to 101° C.).
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:22][CH:23]=1)[N:21]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-chloro-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-chloro-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([C:33]1[C:34]([CH:39]=O)=[N:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:39][C:34]2[C:33]([C:25]([CH3:26])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:24])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(c1ccccc1)c1cccnc1C=O
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 3-(1-Methyl-1-phenyl-ethyl)-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-{(3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])[C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].N(C)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])[C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:24]
Reactant: N#Cc1ccccc1B(O)O
Reactant: NC(=O)c1cccc(N2CC(c3cccc(O)c3)CC2=O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)C
Solvent: ClCCl
Product: N#Cc1ccccc1Oc1cccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.1 %

Procedure:
A mixture of 3-[4-(3-hydroxyphenyl)-2-oxo-pyrrolidin-1-yl]benzamide (30 mg), 2-cyanobenzeneboronic acid (12 mg), and copper acetate (2 eq) was created in a dry tube. The mixture was dissolved in 2 mL CH2Cl2 followed by the addition of (CH3)3N (3 eq). The mixture was stirred at r.t. for 24 h, and then diluted with 10 mL CH2Cl2. The resulting mixture was filtered and washed with NH4Cl solution, water and brine. After removal of solvent, the residue was purified by preparative LC-MS to give 14 mg of the desired product. Yield: 35%.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ncccn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 404.37 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[NH:57]1[CH:61]=[CH:60][N:59]=[CH:58]1>>[N:57]1([CH2:41][CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH2:32][CH2:31][O:30][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19]2)[CH:61]=[CH:60][N:59]=[CH:58]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: c1c[nH]cn1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCn2ccnc2)cc1

Procedure:
Analogously to Example 27a, 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.34 g of 1H-imidazole are reacted. The title compound is obtained as a colourless oil. Rf=0.55 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.37.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+].CO>N1C=CC=CC=1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:24](=[O:26])(=[O:25])[N:23]1[CH3:22]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccccc1C(=O)c1ccc2cccnc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccccc1C1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 43.5 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(2-methoxy-phenyl)-methanone (Intermediate 369) (152 mg, 0.55 mmol), N-methylsulamoyl chloride (Intermediate 213) (212 mg, 1.64 mmol) and NaBH4 (21 mg, 0.55 mmol) in pyridine (10 ml) gave the title compound (85 mg, 44%) after trituration from MeOH.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C@H:20]([NH:22][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccccc1
Temperature: 65 °C
Yield: 28.1 %

Procedure:
To 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (50 mg, 0.249 mmol) in ethanol (2 mL) was added (R)-1-phenyl-ethylamine (66 mg, 0.545 mmol, 2 eq) and the solution was heated at 65° C. for 15 h. The cooled solution was concentrated under vacuum and the resulting oil was taken up in methanol, added to a strong cation exchange (SCX) column and washed with methanol (50 mL). The product was eluted with 1 N ammonia in methanol (50 mL) and concentrated under vacuum. The crude product was absorbed onto Silica Gel (500 mg), added to a Biotage SNAP-10 g column and eluted with 1% to 10% methanol in dichlormethane over 12 column volumes to give: 2-[((R)-1-phenyl-ethylamino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (20 mg, 28% yield). Exact mass calculated for C16H19N3O2 285.15. found 286.5 (ESI, M+H).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 103 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.37–7.23 (m, 14H), 6.93 (d, 1H, J=7.6 Hz), 6.20 (br s, 1H), 3.37 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, 7.2 Hz), 2.45 (m, 1H), 2.30 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.94 (t, 2H, J=11.6 Hz), 1.76–1.53 (m, 6H); ESMS m/e: 484.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:26]([CH2:35][CH3:36])[C:27]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])[CH3:25]>>[CH2:35]([N:26]([CH2:24][CH3:25])[C:27](=[O:28])[CH2:29][CH2:30][CH2:31][C:32]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:33])[CH3:36]
Reactant: CCN(CC)C(=O)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCN(CC)C(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-diethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(diethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=982; RT=1.23 min; UPLC Method I
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10](/C(=C\C=C2\N(CCCS([O-])(=O)=O)C3C=CC4C(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=CC=4C=3C\2(C)C)/C=C/C2C(C)(C)C3C4C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=4C=CC=3[N+]=2CCCS([O-])(=O)=O)[CH:11]=[CH:12][CH:13]=1)([OH:3])=[O:2].[Na+:79].[Na+].[Na+].[Na+].[Na+].Br/[C:85](=[CH:110]\[CH:111]=[C:112]1\[N:113]([CH2:127][CH2:128][CH2:129][S:130]([O-:133])(=[O:132])=[O:131])[C:114]2[C:119]([C:120]\1([CH3:122])[CH3:121])=[CH:118][C:117](S([O-])(=O)=O)=[CH:116][CH:115]=2)/[CH:86]=[CH:87]/[C:88]1[C:96]([CH3:98])([CH3:97])[C:95]2[C:90](=[CH:91][CH:92]=[C:93]([S:99]([O-:102])(=[O:101])=[O:100])[CH:94]=2)[N+:89]=1CCCS([O-])(=O)=O.[Na+].[Na+].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12](/[C:85](=[CH:110]\[CH:111]=[C:112]2\[N:113]([CH2:127][CH2:128][CH2:129][S:130]([O-:133])(=[O:132])=[O:131])[C:114]3[C:119]([C:120]\2([CH3:121])[CH3:122])=[CH:118][C:117]([S:130]([O-:133])(=[O:132])=[O:131])=[CH:116][CH:115]=3)/[CH:86]=[CH:87]/[C:88]2[C:96]([CH3:98])([CH3:97])[C:95]3[C:90](=[CH:91][CH:92]=[C:93]([S:99]([O-:102])(=[O:101])=[O:100])[CH:94]=3)[N+:89]=2[CH2:91][CH2:92][CH2:93][S:99]([O-:102])(=[O:101])=[O:100])[CH:11]=[CH:10][CH:9]=1)([OH:3])=[O:2].[Na+:79].[Na+:79].[Na+:79]
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 14 was prepared analogously to compound 8 (Example 8), except that compound 13 was used as starting materials. UV/vis absorption max: λH2O=649 nm, ε=190,000; λMeOH=650 nm, ε=180,000; MS calculated (found) for (M+1)+935.21 (935.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:23])([C:19]([F:22])([F:21])[F:20])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6]2.[N+](=[CH2:26])=[N-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:23])([C:19]([F:20])([F:21])[F:22])[C:16]([O:18][CH3:26])=[O:17])[CH:7]=[CH:6]2
Reactant: C=[N+]=[N-]
Reactant: COc1ccc2cc(COC(C)(C(=O)O)C(F)(F)F)ccc2c1
Solvent: CCOCC
Product: COC(=O)C(C)(OCc1ccc2cc(OC)ccc2c1)C(F)(F)F

Procedure:
A solution of (±)-2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (1.0 g.) in ether is treated with diazomethane by the process described in Example 18 to give (±)-methyl 2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (0.8 g.) m.p. 60°-62° C. (from methanol at -50° C.).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23]>>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][CH:29]=[C:18]([OH:17])[CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1cccc(O)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 3-hydroxy-DL-phenylalanine to provide the title compound in moderate yield. LCMS m/z 421 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=O)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)c1ncccc1C
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1C(C)NCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B, 1-(3-methylpyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668), (4-aminobutyl)-carbamic acid tert-butyl ester and NaBH(OAc)3 were reacted in CH2Cl2 to obtain {4-[1-(3-methylpyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH:25]N(C)C)[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12].Cl.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([N:8]2[C:20]([OH:21])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=3)[CH:25]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(NN)ncc1Br
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Combined 5-bromo-2-hydrazinyl-4-methylpyridine (6.0 g, 29.85 mmol) and isopropanol (100 mL) and added ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (8.02 g, 32.84 mmol) and HCl solution (aqueous, 1.85%, 49.75 mL) and stirred at room temperature for 2 h, then DIEA (19.40 g, 149.25 mmol) was added. After about 30 minutes the reaction was evaporated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2), the EtOAc layers were combined and washed with brine, dried over Na2SO4 to give a residue which was purified by flash chromatography (petroleum ether:EtOAc 5:1-1:8) to give the title compound (8.67 g, 82.04%).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]4[CH:23]=[N:22][NH:21][C:18]4=[N:19][CH:20]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:24]N1C(=O)CCC1=O>ClC(Cl)C.ClCCl>[I:24][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:11]3[CH:10]=[C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:16]=2)[NH:21][N:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1cccc(-c2cnc3[nH]ncc3c2)c1)N1CCOCC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Morpholin-4-yl-[3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-methanone (2.30 g, 80% pure, ˜6 mmol) and of N-iodosuccinimide (2.50 g, 11.1 mmol) were dissolved in dichloroethane (180 mL). The mixture was stirred under reflux conditions for 5 h, then cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated aqueous solution of sodium thiosulfate (1×) and then with a saturated aqueous solution of sodium bromide (2×), dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with ether (80 mL) and dried to afford [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone as a beige powder (2.881 g, 88% yield over two steps). 1H-NMR (500 MHz, d6-DMSO) δ14.19 (s, 1H), 8.92 (d, 1H), 8.14 (d, 1H), 7.91 (m, 1H), 7.83 (m, 1H), 7.59 (ddd, 1H), 7.44 (dt, 1H), 3.75-3.35 (m, 8H).
Reaction SMILES: C([O-])(=O)C.[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH2:10])=[NH2+:9])#[N:6].C(N(CC)CC)C.BrBr.[S-:23][C:24]#[N:25].[K+]>CO>[NH2:25][C:24]1[S:23][N:10]=[C:8]([C:7](=[N:11][O:12][CH3:13])[C:5]#[N:6])[N:9]=1
Reactant: N#C[S-]
Reactant: CON=C(C#N)C(N)=[NH2+]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C#N)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 174.9 %

Procedure:
To a solution of 2-cyano-2-(methoxyimino)acetamidinium acetate (12.5 g) dissolved in methanol(100 ml) was added triethylamine(23.4 ml). Thereafter, bromine (12.9 g) was added slowly in small portions at -15° C., and the mixture was stirred for 5 minutes at -15°~-10° C., Potassium thiocyanate(3.7 g) dissolved in methanol(55 ml) was then added dropwise to the mixture at temperatures of -10° to -5° C., and the mixture stirred for 2 hours at 0° C. The reaction mixture was poured into ice water (1.2 l), and stirred for 30 minutes. The precipitates were filtered and dired to give the above-indicated compound (12.2 g) in pale brown.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>C1COCC1>[C:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[C:2]1=[O:1])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: C=CC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (500 mg, 2.19 mmol), THF (10 mL) and a 6 M solution of LiHMDS in THF (0.475 mL, 2.85 mmol). The reaction was stirred at rt for 1 hr before it was cooled to 0° C. Then, methyl acrylate (0.237 mL, 2.63 mmol) was added to the reaction and the reaction was slowly warmed up to rt and stirred at rt overnight. The reaction was concentrated and purified using RP prep-HPLC (Method A) to give (S)-methyl 3-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)propanoate (140 mg, 0.445 mmol, 20.3% yield) as a white solid. Anal. Calcd. for C15H26N2O5 m/z 314.3. found: 315.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.96 (d, J=5.5 Hz, 1H), 4.34 (dd, J=11.0, 6.0 Hz, 1H), 3.77 (ddd, J=13.6, 6.7, 6.6 Hz, 1H), 3.69 (s, 3H), 3.61 (ddd, J=13.9, 7.1, 7.0 Hz, 1H), 3.57-3.47 (m, 1H), 3.33 (dd, J=14.8, 4.4 Hz, 1H), 2.65-2.50 (m, 2H), 2.04 (d, J=13.2 Hz, 1H), 1.94 (d, J=13.7 Hz, 1H), 1.88-1.74 (m, 2H), 1.50-1.40 (m, 9H), 1.41-1.25 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 173.15, 172.24, 155.16, 79.35, 53.34, 51.80, 49.88, 45.50, 32.51, 28.39, 27.86, 27.74.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]1([CH2:15][CH:16]=O)[CH2:14][O:13][CH2:12]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH2:15][C:11]1([CH3:10])[CH2:14][O:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CC=O)COC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC1(C/C=N/CC(=O)OC(C)(C)C)COC1
Yield: 100.6 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with (3-methyl-oxetan-3-yl)-acetaldehyde (0.8 g, 7 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(3-methyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.6 g, 100%).