Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and 4-bromophenyl acetohydroximoyl chloride (168 mg, 0.677 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 15 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (33 mg, 24%).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:24]>>[C:54]([O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:24])=[CH:48][CH:49]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 81 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=1>>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([Cl:3])=[O:14])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(C)C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
160.65 g (1.35 mol) of thionyl chloride are placed in a 1 liter three-necked flask fitted with a mechanical stirrer and a condenser. 164.2 g (0.9 mol) of p-methylphenylpropionic acid are added little by little thereto at room temperature. After 4 hours, the reaction is terminated by heating at 60° C. for 1 hour. Excess SOCl2 is removed by distillation/n vacuo. In that manner 164.5 g of p-methylphenylpropionic acid chloride are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1cnc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)COCc3ccccc3)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Temperature: 80 °C

Procedure:
A vigorously stirred suspension of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (3.82 g, 8.12 mmol) and 2N KOH (40.6 ml, 0.081 mol) in MeOH (40 mL) was heated at 80° C. for approximately 4 h. After cooling to room temperature, the reaction mixture was acidified to pH 6 with 2N HCl and extracted with ethyl acetate (x3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was used without further purification in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([O-])=O.[Na+].[ClH:14]>>[ClH:14].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(NN)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-methylaniline (10.2 g) was suspended in 6N HCl (85 mL) and cooled to 0° C. A solution of sodium nitrite (4 g in 40 mL H2O) was added over 10 min. The reaction was stirred for 15 min at 0° C. followed by the addition of stannous chloride dihydrate (36 g in 25 mL 12N HCl.) The reaction was stirred for 2 hr at 0° C. The reaction was filtered and the filter cake washed with cold H2O to afford 4-bromo-3-methylphenylhydrazine hydrochloride (Cmpd 9a, 20 g) as a tan solid.
Reaction SMILES: Cl.[CH:2]1([CH:6]([NH2:8])[CH3:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.C1COCC1.Cl[C:22]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:23]=1[C:24]([C:26](=[CH:32]OCC)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25]>O>[CH:2]1([CH:6]([N:8]2[C:22]3[C:23](=[CH:36][C:37]([F:41])=[C:38]([F:40])[CH:39]=3)[C:24](=[O:25])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32]2)[CH3:7])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(N)C1CCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C(C)C2CCC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
1.02 g of 1-cyclobutylethylamine hydrochloride and 1.05 ml of triethylamine were added under ice-cooling to a 15 ml THF solution of 2.0 g of ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-ethoxyacrylate, followed by overnight stirring at room temperature. Water was added to the resulting reaction mixture, followed by extraction with ether and washing with water and aqueous saturated sodium chloride. After drying over anhydrous magnesium sulfate, concentration under a reduced pressure was carried out. 315 mg of 55% sodium hydride was added under ice-cooling to a 30 ml dioxane solution of the resulting residue, followed by overnight stirring at 80° C. The reaction mixture was poured into 1 M hydrochloric acid, followed by extraction with chloroform and washing with water and aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent concentration under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 1.13 g of ethyl 1-(1-cyclobutylethyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: [C:1]([Si:5]([CH3:60])([CH3:59])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53]([O:55]C)=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].O.C(N(CC)CC)C.[Br-].[Li+]>C(#N)C>[C:1]([Si:5]([CH3:59])([CH3:60])[O:6][CH2:7][CH2:8][C@:9]([OH:58])([C@@H:17]([C:38](=[O:57])[NH:39][C@H:40]([C:53]([OH:55])=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:30][CH2:29][CH2:28][O:27]1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
No. 5327507 (Compound C; 1.09 g, 1.27 mmol) was dissolved in acetonitrile (10.9 mL), and then water (0.109 mL), triethylamine (1.06 mL, 7.61 mmol), and lithium bromide (2.91 g, 33.5 mmol) were added at room temperature. The reaction solution was stirred at 50° C. for 3.5 hours, then cooled to room temperature, quenched by the addition of 1 M hydrochloric acid (30 mL), and then extracted with ethyl acetate (100 mL). The organic layer was washed twice with water (100 mL) and then with a saturated aqueous solution of sodium chloride (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.08 g (purity 71%, ESI (LC/MS positive mode) m/z 845 (M+H); Rt 3.32 min.) of Compound I, tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH3:8])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:42][CH2:43][C:44]3[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=3[CH3:50])=[O:15])=[CH:16][CH:17]=2)[CH3:8])=[CH:18][CH:19]=1
Reactant: CC(Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(F)cc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
A mixture of 4-(1-(4-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(4-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (115 mg, 29%). LRMS (M+H+) m/z: calcd 394.17. found 394. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=5.1 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.04-6.85 (m, 4H), 5.83 (s, 1H), 5.47 (q, J=6.6 Hz, 1H), 4.26 (d, J=5.1 Hz, 2H), 2.16 (s, 3H), 2.10 (s, 3H), 1.52 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]([CH2:11][C:12]([C:39]3[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([F:54])=[CH:52][CH:51]=[C:50]([Cl:55])[C:49]=4[F:56])[CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=O)(C)(C)C.ClC(Cl)(Cl)C(NC(=O)[O-])(C)C>C1COCC1.CC(O)=O.[Zn]>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C:13]2[CH:14]3[NH:16][CH:10]([CH2:11][C:12]=2[C:39]2[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([F:54])=[CH:52][CH:51]=[C:50]([Cl:55])[C:49]=4[F:56])[CH:40]=2)[CH2:9][NH:8][CH2:15]3)=[O:38])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCOc4c(F)ccc(Cl)c4F)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Agent: CC(C)(NC(=O)[O-])C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(C1=C(c2cc(CCCOc3c(F)ccc(Cl)c3F)no2)CC2CNCC1N2)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
This compound is prepared from compound F9, according to the above-described procedure B. After cleaving the Boc-group the trichloro-tert-butylcarbamate was cleaved using Zn-powder in THF/AcOH 3:1. LC-MS: tR=0.90 min; ES+: 637.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)[CH3:22].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:34](=[O:35])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH3:22])[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(N(C)CCN(C)CCCNCCc2cc(OC)c(OC)cc2N)cc1OC
Product: COc1ccc(N(C)CCN(C)CCCN2CCc3cc(OC)c(OC)cc3NC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-dimethoxyphenyl)-ethylamino)-propyl]-N-[2-(N-methyl-3,4-dimethoxy-phenylamino)-ethyl]-methylamine and carbonyldiimidazole analogously to Example 56.
Reaction SMILES: CC(C)(S([NH:6][CH2:7][C:8]1[N:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[C:17]([O:19][CH3:20])=[O:18])=O)C.Cl.C(OCC)C.C([O-])(O)=O.[Na+]>ClCCl>[NH2:6][CH2:7][C:8]1[N:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc2n(c1CNS(=O)C(C)(C)C)CCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc2n(c1CN)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 238b (3.5 g, 11.2 mmol), saturated HCl/diethyl ether solution (15 mL), and dichloromethane (15 mL). The mixture was stirred at room temperature for 4 h. After the reaction was completed, saturated aqueous NaHCO3 solution (50 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was evaporated under reduced pressure to afford 238c (2.2 g, 94%), which was directly used in the next step without further purification. MS: [M-NH2]+ 192.1. 1H NMR (500 MHz, MeOD) δ 6.28 (s, 1H), 4.38 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.84 (s, 3H), 2.78 (t, J=6.5 Hz, 2H), 2.06-2.02 (m, 2H), 1.87-1.82 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[OH-].[Na+:29]>>[Na+:29].[I:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][C:3]([O-:27])=[O:2])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CCCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Yield: 37.9 %

Procedure:
The title compound (15 mg. 38%) was prepared from the compound from step 1 (39 mg, 0.081 mmol) and 1N NaOH (0.11 mL, 0.11 mmol) by the procedure described in Example 2: MS (ESI) m/z 467 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 1.59 (m, 2H), 1.83 (t, J=7.2 Hz, 2H), 2.27 (t, J=7.6 Hz, 2H), 2.47 (t, J=4.8 Hz, 4H), 3.09 (t, J=4.8 Hz, 4H), 6.74 (dd, J=2.0, 6.8 Hz, 2H), 6.91-6.98 (m, 4H), 7.63 (dd, J=2.4, 6.4 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S(C(F)(F)F)(=O)=O.F[N+:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[N:12][N:11]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: F[n+]1ccccc1
Reactant: COc1cc(-c2c[nH]nn2)ccc1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CO
Product: COc1cc(-c2cnn(-c3ccccn3)n2)ccc1-c1ccccn1
Reaction time: 8 h

Procedure:
To a solution of 2-[2-methoxy-4-(1H-1,2,3-triazol-4-yl)phenyl]pyridine (180 mg, 0.71 mmol) in anhydrous MeOH was added Cs2CO3 (462 mg, 1.42 mmol) and 1-fluoropyridinium triflate (350 mg, 1.42 mmol). The resulting reaction mixture was stirred overnight. The mixture was partitioned between 10% aqueous NaOH (10 ml) and EtOAc (60 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel (1:2 hexane-ethyl acetate) to afford 2-[4-(3-methoxy-4-pyridin-2-ylphenyl)-2H-1,2,3-triazol-2-yl]pyridine which was dissolved in ether and HCl (1N in ether) was added. The solution was filtered to give a HCl salt as white solid. 1H NMR (500 MHz, CD3OD) δ 8.86-8.47 (m, 1H), 8.72-8.68 (m, 1H), 8.64-8.62 (m, 2H), 8.39-8.37 (m, 1H), 8.26-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.07-8.04 (m, 1H), 8.02 (m, 1H), 7.91-7.80 (m, 2H), 7.60 (m, 1H). MS (ESI) 330 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][N:12]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:19])=[O:5])=[O:10])=[N:12][CH:13]=[C:14]([OH:18])[CH:15]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncc(O)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1ncc(O)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 28, (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) at room temperature is added trifluoroacetic acid (1 mL). The reaction is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The solid that remains is collected by filtration, washed with Et2O to afford 0.070 g (89% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 10.86 (1 H, br s), 9.00 (1 H, t, J=6.1 Hz), 7.77 (1 H, d, J=2.4 Hz), 6.69 (1 H, d, J=2.4 Hz), 3.95 (1 H, d, J=6.2 Hz). HPLC-MS: m/z 213 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound, mp 138° C., was prepared from N-(2-hydroxyethyl)phthalimide (9.6 g) and 4-fluorobenzaldehyde (6.2 g, 5.3 ml) by a procedure similar to that described in Procedure 2.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>ClCCl>[CH2:21]([NH:25][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH2:22][CH2:23][CH3:24]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 12 h
Yield: 71.8 %

Procedure:
In 100 ml of dichloromethane was dissolved 2.28 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.38 g of anhydrous potassium carbonate and 1.46 g of n-butylamine, and the mixture thus obtained was stirred at a temperature of 20° C. to 25° C. for 12 hours. The reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the dichloromethane was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 1.90 g of N-n-butyl-5-isoquinolinesulfonamide i.e., Compound (27) in a yield of 72%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[N:8]2)=[O:4].[OH-].[Na+].Cl>C(O)C>[N:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=2)[N:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc2nccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nccnc2c1
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a solution of quinoxaline-6-carboxylic acid methyl ester (2084 mg, 11.07 mmol) in ethanol (25 mL) was added an aqueous solution of 1N sodium hydroxide (25 mL), and the solution was stirred for 4 hours under reflux. 1N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, then, the precipitated solid was collected by filtration, washed with water and isopropanol, then dried to obtain the title compound (1477 mg, 8.479 mmol, 76.6%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=O
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=S
Yield: 86.1 %

Procedure:
To a solution of 20 g (0.07 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)one in 200 ml of toluene was added a mixture of 9.55 g (0.05 mole) of phosphorus pentasulfide and 9.5 g of potassium sulfide which had been ground together. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a yellow solid. Recrystallization from absolute ethanol gave 12.5 g (68%) of the product, m.p. 102°-104° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[K+]>O.CCO>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(C(=O)O)cc1
Yield: 78.6 %

Procedure:
A suspension of 4-bromomethylbenzoic acid (25.26 g, 0.12 mol) and KCN (20 g, 0.31 mol) in 5:7 H2O/EtOH (60 mL) was heated to 75°-80° C. for four hours. The cooled reaction was partially concentrated, H2O added, and extracted 1× with EtOAc. After acidification of the aqueous layer, the resulting precipitate was filtered and washed well with H2O to yield 13.6 g; 4 EtOAc extractions of the filtrate yielded an additional 2.7 g. Recrystallization of the combined solids from H2O/EtOH using activated charcoal and filtering through Celite afforded 15.20 g of 4-cyanomethylbenzoic acid.