Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1.O>CN(C=O)C>[CH2:1]([O:8][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][N:17]=[C:12]([Cl:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)nc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
Benzyl alcohol (5.57 g) was added to a suspension of sodium hydride (oil, 60%, 2.06 g) in DMF (100 mL) by small portions at 0° C., and the obtained mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to 0° C., 2,4-dichloro-5-nitropyrimidine (10.0 g) was added thereto, and the obtained mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (670 mg). 1H NMR (300 MHz, DMSO-d6) δ 5.62 (2H, s), 7.24-7.73 (5H, m), 9.28 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23].CN1CCOCC1.[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
A stirred solution of methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (0.2 g.) in dichloromethane (5 ml.) under an atmosphere of nitrogen, was treated with N-methylmorpholine (0.25 g.), followed by hexanoyl chloride (0.103 g.). After being stirred for 2 hours, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2x20 ml.). The combined organic extracts were dried (MgSO4) and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (75 ml.), eluting with 6:4 v/v ethyl acetate:hexane, to give the title compound (0.24 g., 92%) as a colorless oil: NMR: 0.83 (t,3 H, CH2.CH3), 1.36 (m,4 H, CH2.CH2.CH3), 1.57 (quintet,2 H, CH2.CH2CON), 2.24 (t, 2 H, CH2.CON), 3.80 (s,3 H, COOCH3), 3.90 (s,3 H, OCH3), 3.99 (s,2 H, CH2.Ar), 7.1 (m, 2 H), 7.21 (m,2 H), 7.44 (m,2 H), 7.69 (s,1 H,H4 -indole), 9.59 (s,1 H, CONH), 10.77 (s,1 H, H1 -indole).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4].Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of 4.80 g (11.82 mmol) of the product of Example 17 dissolved in 5.0 mL of DMF was added 2.04 g (12.41 mmol) of 3-picolyl chloride hydrochloride and 4.89 g (35.46 mmol) of potassium carbonate. The reaction mixture was then stirred at room temperature for 18 h, diluted with water and extracted with ether. The oragnics were then extracted with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide 4.16 g (71%) of the desired product as a tan solid. Electrospray Mass Spec: 498 (M+H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7]3([O:32][C@H:8]3[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([C@H:8]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Reactant: NCCc1c[nH]cn1
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
5,6α-epoxicholestan-3β-yl acetate (9.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl acetate as a white solid (7.5 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>ClCCl>[CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([N:23]([O:24][CH3:25])[CH3:22])=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COc1cnccc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-isobutoxyisonicotinic acid (2.2 g, 11.2 mmol) and oxalyl chloride (7 g, 55 mmol) in 25 mL of dichloromethane was stirred at room temperature for 1 h. The resulting solution was concentrated down under reduced pressure and the residue was re-dissolved in 50 mL of dichloromethane. To this solution were added N,O-dimethylhydroxyl-amine hydrochloride (4.5 g, 46.4 mmol) and pyridine (5 mL) at 0° C. The reaction was allowed to warm up to room temperature over 30 min period, and quenched with 2 mL of water. The resulting mixture was bacified with 1 mL 10% KOH solution (pH=10), the layers were separated, and the aqueous layer was washed twice with 20 mL portions of dichloromethane. The combined dichloromethane washes were dried over sodium sulfate, and concentrated down under reduced pressure, resulting in 1.8 g (67%) of 3-isobutoxy-N-methoxy-N-methylisonicotinamide. 1H-NMR (400 MHz, d6-DMSO): δ 8.46 (s, 1H), 8.25 (d, 1H), 7.45 (d, 1H), 3.96 (d, 2H), 3.43 (s, 3H), 2.76 (d, 3H), 2.05 (m, 1H), 0.94 (d, 6H). MS (EI) for C12H18N2O2: 239 (MH+).
Reaction SMILES: O1CC1CO[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:31]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:17][CH:23]([OH:24])[CH2:31][C:15]3[CH:14]=[CH:13][CH:12]=[C:9]4[C:10]([NH:6][C:7](=[O:16])[C:8]=34)=[O:11])[CH2:27][CH2:26]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CO1
Solvent: CCO
Product: O=C1NC(=O)c2c(CC(O)CN3CCC(OC(c4ccccc4)c4ccccc4)CC3)cccc21

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 2.58 ml of epibromohydrin was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected to yield 3.7 g of N-(2-oxiranylmethoxy)phthalimide. 0.61 g of N-(2-oxiranylmethoxy)phthalimide and 0.802 g of 4-(diphenylmethoxy)piperidine were dissolved n 10 ml of ethanol, followed by thermal refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected to yield 1.30 g of N-[3-[4-(diphenylmethoxy)piperidino-2-hydroxypropyl]phthalimide as an oily substance. This oily substance was dissolved in 10 ml of ethanol; 0.14 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethanol was added to the residue; the crystal precipitated was collected, dissolved in 3 ml of a 1 N aqueous solution of sodium hydroxide and 10 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 0.76 g of the title compound.
Reaction SMILES: [C:1](OCC)(=[O:3])C.Cl.F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][C@H:24]([O:28][CH2:29][C:30]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=4[C:32]([OH:34])=[O:33])[CH2:23]3)[N:19]=2)=[CH:11][CH:10]=1>C[O-].[Na+].CO>[CH3:1][O:3][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][C@H:24]([O:28][CH2:29][C:30]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=4[C:32]([OH:34])=[O:33])[CH2:23]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(CO[C@@H]3CCC[C@H](OCc4cccc(C)c4C(=O)O)C3)co2)cc1

Procedure:
170 mg (0.39 mmol)of6b were heated in 4 ml of 5.6 M NaOMe/MeOH solution at an oil bath temperature of 120° C. for 20 hours. Ethyl acetate and 2 N HCl were added, and the mixture was then worked up analogously to the synthesis of 6b. This gave 7b as a colorless amorphous solid. TLC: (methylene chloride/-methanol/conc. ammonia, 30/5/1). Rf˜0.3. C26H29NO6 (451.52) MS(ESI): 452 (M+H+).
Reaction SMILES: Cl.C([N:9]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)C1C=CC=CC=1.O>CO.[Pd]>[C:17]1([CH:11]2[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][NH:9][CH2:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1CCCNCC1c1ccccc1

Procedure:
22.1 g of 1-benzyl-3-phenyl-perhydro-azepin-4-one hydrochloride are dissolved in 250 ml of methanol and 10 ml of water and hydrogenated with 2.5 g of Pd/C (10%) for 3 hours under 5 bar of H2. Then another 2.5 g of catalyst are added and the hydrogenation step is repeated. The catalyst is filtered off and the mixture is evaporated down. The residue is recrystallised from ethanol. Yield: 8.2 g
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]1[CH2:51][C@@:49]2([CH3:50])[C@@H:45]([CH2:46][CH2:47][C@@H:48]2[OH:52])[C@@:44]2([CH:53]=[CH2:54])[C@H:35]1[C:36]1[CH:37]=[CH:38][C:39]([OH:55])=[CH:40][C:41]=1[CH2:42][CH2:43]2>>[CH3:26][N:27]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]1[CH2:51][C@@:49]2([CH3:50])[C@@H:45]([CH2:46][CH2:47][C@@H:48]2[OH:52])[C@@:44]2([CH:53]=[CH2:54])[C@H:35]1[C:36]1[CH:37]=[CH:38][C:39]([OH:55])=[CH:40][C:41]=1[CH2:42][CH2:43]2
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN(C)CCCCCCCC(F)(F)C(F)(F)F)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with 8,8,9,9,9-pentafluorononyl tosylate analogously to instructions 22.1, 39 mg of amine 31b yields 22 mg of amine 36b as a colorless foam (GC-MS: m/z theor.: 627, pract.: 627).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:28])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 g (25 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman (Ex. 1 e) were introduced in portions at 10° C. into a suspension of 1.2 g (30 mmol) of sodium hydride (60 percent dispersion) in 75 ml of DMA. After stirring at RT for 2 h, 1.9 ml (30 mmol) of methyl iodide were added dropwise, the temperature rising to 50° C. The mixture was then heated to 50° C. for 2 h, concentrated in vac., the residue was treated with water, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed on silica gel using n-heptane/EA (2:1). 7.4 g of product were crystallized from appropriate fractions using petroleum ethendusopropyl ether (1:1), m.p. 114-116° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCCCCC>C(Cl)Cl>[Br:8][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[P:19](=[O:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (6.7 g, 37.6 mmol) was added to a solution of (3,5-dimethoxyphenyl)diphenylphosphine oxide (12.3 g, 36.4 mmol) in CH2Cl2 (140 ml) at 0° C. The resulting suspension was stirred at 0° C. for 1 h. Na2CO3 (saturated, 40 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (40 ml×2). The combined organic layer washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow solid (14.3 g, 94% yield). It was sufficiently pure for the next step. The pure sample was obtained by crystallization from CH2Cl2/Hexane (1/15). 1H NMR (300 MHz, CD2Cl2) δ: 7.73-7.67 (m, 4H), 7.62-7.56 (m, 2H), 7.53-7.46 (m, 4H), 6.69 (d, J=3 Hz, 1H), 6.57 (dd, J1=3 Hz, J2=14.1 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H). 31P NMR (121.5 MHz, CD2Cl2) δ: 30.72.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:29]=[N:28][C:14]2[NH:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[Cl:27])[C:13]=2[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[CH2:19][N:18]1[CH2:17][CH2:16][NH:15][C:14]2[N:28]=[CH:29][C:11]([C:10]#[C:9][CH2:8][NH2:7])=[CH:12][C:13]1=2
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 37 %

Procedure:
{3-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]prop-2-ynyl}carbamic acid tert-butyl ester (19 mg), trifluoroacetic acid (250 μL) and CH2Cl2 (1 mL) were stirred under nitrogen at room temperature for 1.5 hours. 2 N NaOH (2 mL) and CH2Cl2 (approx. 10 mL) were added. The organic phase was isolated, washed twice with H2O, washed once with brine, dried over sodium sulfate, filtered and then purified by normal phase column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound as an off-white solid (37% yield). M.p.=183° C., LCMS: m/z=347.35 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.42 (2H, t, J=4.8 Hz), 3.61 (4H, m), 4.41 (2H, s), 5.04 (1H, bs), 6.42 (1H, s), 7.21 (2H, m), 7.34 (1H, d, J=8.3 Hz), 7.59 (1H, s, J=1.0 Hz).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.Cl.[F:44][CH2:45][CH2:46][NH2:47]>CC(N(C)C)=O>[F:44][CH2:45][CH2:46][NH:47][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCCF
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCF
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-fluoro-ethylamine hydrochloride salt (32 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:14][CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cncc(Br)c1
Temperature: 25 °C
Yield: 148.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-3-hydroxypyridine (1.90 g, 10.92 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.52 g of an 80% dispersion in mineral oil, 17.47 mmol) in DMF (14 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1H. To this slurry was added dropwise over 5 min 1-choro-3-iodopropane (2.68 g, 13.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water (30 mL) was carefully added, followed by saturated NaCl solution (20 mL). The resulting mixture was extracted with ether (5×25 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (4.07 g). The product was used in the next step without further purification. EI-MS: m/z (relative intensity) 251 (M+, 31.89%), 249 (M+, 23.99%), 175 (65.68%), 173 (67.42%), 94 (37.06%), 41 (100.00%).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.O.[H][H]>[Ni].C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[CH:12]=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: [H][H]
Reactant: CNc1cc(Cl)[n+](C)nc1-c1ccccc1
Agent: [Ni]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1cc[n+](C)nc1-c1ccccc1
Reaction time: 24 h

Procedure:
15 parts of 1-methyl-3-phenyl-4-methylamino-6-chloropyridazinium perchlorate, 100 parts of water, 5 parts of triethylamine and about 2 parts of Raney nickel are treated at room temperature in a shaking apparatus with hydrogen at atmospheric pressure. After 24 hours the reaction mixture is suction filtered, the residue is boiled with 200 parts of methanol and filtered and the filtrate is concentrated and cooled. 10.3 parts (76.6% of theory) of 1-methyl-3-phenyl-4-methylaminopyridazinium perchlorate is obtained; C12H14O4N3Cl, melting point 155° to 157°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10]([O-:13])([O-])=[O:11].[K+].[K+].Cl>CCO.O>[C:3]([O:13][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:11])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C(O)C1CCCNC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 249.7 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of piperidine-3-carboxylic acid (4.0 g, 30.39 mmol, 1.00 equiv, 98%) in EtOH (70 mL), tert-butoxycarbonyl (8.2 g, 36.86 mmol, 1.21 equiv, 98%) and K2CO3 (4.3 g, 30.54 mmol, 1.00 equiv, 98%). The resulting mixture was stirred overnight at room temperature overnight. Then, the mixture was diluted with water. The pH was adjusted to 3 with aqueous 10% HCl resulting in a precipitate. The mixture was then filtered to collect solids that were washed with water and dried in a vacuum oven under reduced pressure to afford 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as white solid (8.7 g).