Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Br[C:59]1[C:64]([F:65])=[CH:63][C:62]([C:66]([F:69])([F:68])[F:67])=[CH:61][N:60]=1>>[F:65][C:64]1[C:59]([NH:35][CH2:36][C@@H:37]2[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]2[C:44]([C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)=[O:45])=[N:60][CH:61]=[C:62]([C:66]([F:68])([F:67])[F:69])[CH:63]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].Cl>C(Cl)Cl.CN(C=O)C>[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH:31][C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[C:12]([O:14][CH3:15])=[O:13])=[O:7]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1ccc(OC)c(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C(=O)Nc2c(F)cccc2F)c1
Yield: 52 %

Procedure:
2-(Methyloxy)-5-[(methyloxy)carbonyl]benzoic acid (1.96 g, 9.33 mmol) was suspended in 60 mL of DCM with stirring. DMF (0.036 mL, 0.46 mmol) was added via syringe. Oxalyl chloride (7.0 mL, 2.0M in dichloromethane, 14 mmol) was added dropwise via addition funnel. The addition funnel was rinsed with 10 mL of DCM. The reaction was stirred for 2 hours and concentrated in vacuo. The resultant solid was further dried under high vacuum pressure. The solid was dissolved in 60 mL of DCM with stirring. Pyridine (3.8 mL, 47 mmol), (4-dimethylamino)pyridine (0.0570 g, 0.467 mmol), and 2,6-difluoroaniline (3.0 mL, 28 mmol) were added to the solution. The reaction was stirred for 18 hours and poured into 1N HCl. The layers were separated, and the aqueous layer was washed once with DCM and once with diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 1.56 g (52%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.8, 2.0 Hz, 1H), 7.38 (m, 1H), 7.31 (d, J=88 Hz, 1H), 7.22-7.13 (m, 2H), 3.97 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][N:38]=[C:37]1SC)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CO.C(Cl)(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][N:38]=[C:37]1[NH:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CSC1=NCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(NC2=NCCN2C(=O)OC(C)(C)C)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of 6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (Example 11) (49 mg, 0.125 mmol) and 2-methylsulfanyl-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (25.5 mg, 0.125 mmol) in MeOH (2 ml) was heated at 70° C. for 3 h, then cooled to rt and stirred overnight. The reaction mixture was diluted with CHCl3 (25 ml), washed with saturated NaHCO3 (10 ml) dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give 424A (22 mg, 97%) as pale yellow flakes (5% MeOH—CHCl3). It has a retention time of 6.82 min (standard LC1 method, 8 min run). MS Found: (M+M)+=523.9
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (36 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described according to Example 69 to give the free base of the product, which was crystallized from dichloromethane/ethyl acetate to give 45 mg (50%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].C(O)C.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=1>C(O)C.C(O)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[NH:2][N:3]=[CH:17][C:15]1[N:16]=[C:12]([CH3:11])[NH:13][CH:14]=1)[CH3:7]
Reactant: CCOC(=O)NN
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1c[nH]c(C)n1

Procedure:
A solution of 16.68 gm. of ethyl carbazate in 50 ml. of hot ethanol is added to a solution of 16.50 gm. of 2-methyl-4-imidazolecarboxaldehyde in 100 ml. of hot ethanol containing 2 drops of acetic cid. The reaction is carried out as described in Example 32 giving the desired product, m.p. 210.5°-211.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)([CH3:24])[CH3:23]
Reactant: Cc1cccc(C(=O)NNC(C)C)c1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (150.0 mg, 0.52 mmol), N′-isopropyl-3-methylbenzohydrazide (150.0 mg, 0.78 mmol) and HATU (296.6 mg, 0.78 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.78 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-methylbenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (92.0 mg, 48.3%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:26][NH:27][CH:28]1[CH2:31][NH:30][CH2:29]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:30]5[CH2:31][CH:28]([NH:27][CH3:26])[CH2:29]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNC1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Product: CNC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 11, but starting with 1.5 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.13 g of 3-(methylamino)azetidine dihydrochloride. The reaction mixture is stirred for 1 hour at 40° C. 1 g of 1-cyclopropyl-7-fluoro-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 262° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH3:18])[CH:3]=1.C[O:20]B(OC)OC.Cl>O1CCCC1.C([Li])CCC.CCCCCC>[CH2:10]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:20])=[CH:3][C:4]=1[CH2:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Yield: 92.9 %

Procedure:
Then, 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene was dissolved in 250 ml of tetrahydrofuran, to which 69 ml of a solution of n-butyl lithium in hexane (1.69 mol/l) was added dropwise with stirring at -70° C. After further stirring at -70° C. for 2 hours, a solution of 12.1 g of trimethoxyboran dissolved in 50 ml of tetrahydrofuran was added dropwise to the reaction solution. After completion of the dropwise addition, the reaction mixture was returned to room temperature and stirred for 1 hour, which was poured into ice water, weakly acidified by the addition of 10% hydrochloric acid and extracted twice with 500 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated. To the residue was added 120 m of toluene, to which 33 ml of 30% aqueous hydrogen peroxide solution was added dropwise with heating at 0° C. under stirring. After heating under reflux for 1 hour, the reaction mixture was returned to room temperature, washed once with water, twice with 10% aqueous ammonium ferrous sulfate solution and further once with water, and the toluene layer was dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.2 g of 4-benzyloxy-3-ethyl-5-methylphenol (yield, 93%).
Reaction SMILES: [C@@H:1]1(C(O)=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=CC(P([N:24]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[F:27][C:28]([F:33])([F:32])[C:29](O)=[O:30].C([O-])([O-])=O.[K+].[K+]>ClC1C=CC=CC=1.Cl[Cu].C(N(CC)CC)C>[C@@H:1]1([NH:24][C:29](=[O:30])[C:28]([F:33])([F:32])[F:27])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)[C@H]1CC=CCC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: O=C(N[C@H]1CC=CCC1)C(F)(F)F
Temperature: 80 °C

Procedure:
50 g of 3-cyclohexene-1(R)-carboxylic acid and 425 ml of chlorobenzene were charged to a flask at 20-25° C. and the mixture obtained was stirred. To the mixture obtained 110 ml of triethylamine was added dropwise followed by 25 ml of chlorobenzene. The mixture obtained was warmed to 78 to 82° C. and 109.2 g of DPPA was added in a dose controlled fashion, maintaining the temperature at 80 to 90° C. and steady gas evolution and a 20 ml of chlorobenzene line rinse was given. The mixture obtained was stirred at 78 to 82° C. for 1 h until complete determined by TLC. The mixture obtained was cooled to approximately 70° C. and 226 g of trifluoroacetic acid in 34 ml of chlorobenzene was added dropwise maintaining the temperature at 70 to 80° C., followed by 1.57 g of CuCl and a 25 ml chlorobenzene line rinse. The mixture obtained was stirred at 90 to 95° C. for 2 h and the reaction was followed by TLC until completion. The mixture obtained was cooled to 15 to 25° C. and 375 ml of 20% aqueous K2CO3 solution added and the mixture obtained was stirred for 15 min. The layers obtained were separated and to the upper organic layer obtained was added 375 ml of 20% aqueous K2CO3 solution. The mixture obtained was filtered through celite to remove residual solid and the celite was washed with 50 ml of chlorobenzene. The layers obtained were separated. The combined lower aqueous layers obtained were back extracted with 250 ml of chlorobenzene and the combined organic phases obtained were washed with 500 ml of 0.5 M phosphoric acid. The aqueous layer obtained was back extracted with 300 ml of chlorobenzene and the combined organic phases obtained were washed with 500 ml of 5% aqueous NaCl solution.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](O)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].P(Cl)(Cl)([Cl:23])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([Cl:23])=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCCCCl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl

Procedure:
A mixture of 3.5 g (12 mmol) of 7-(3-chloro-propoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 28 ml of phosphorous oxychloride was refluxed for 1.5 hr. Excess reagent was removed at reduced pressure. The residue was mixed with ice cold dilute sodium hydroxide and ethyl acetate. The mixture was extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts were washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and filter through a short column of silica gel. Solvents were removed giving 3.2 g of the title compound as a pink solid that is used with additional purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[OH:24]>ClCCCl.O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[C:18]=2[OH:24])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Oc1cccc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(F)c(F)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of aluminium chloride (7.66 g, 57.4 mmol, 1.5 eq.) and (4-chlorophenyl)acetyl chloride (8.7 g, 46 mmol, 1.2 eq.) in 1,2-dichloroethane (75 ml) is stirred at 0° C. for 30 min. A solution of 2,3-difluorophenol (5 g, 38.4 mmol) in 1,2-dichloroethane (25 ml) is added to the reaction mixture, which is heated in an oil bath at 90° C. overnight. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford a brown solid. This is triturated with hexane/ethyl acetate (9:1), filtered and dried to afford the title compound as a pale brown fine solid which is 87% pure by HPLC analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]=[C:4]1[CH2:9][CH2:8][N:7]([N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C[Si]([C:18]#[N:19])(C)C>O>[CH3:11][N:10]([CH3:12])[N:7]1[CH2:8][CH2:9][C:4]([NH:3][N:2]([CH3:13])[CH3:1])([C:18]#[N:19])[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)C#N
Reactant: CN(C)N=C1CCN(N(C)C)CC1
Solvent: O
Product: CN(C)NC1(C#N)CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
2.25 g [4-(Dimethyl-hydrazono)-piperidin-1-yl]-dimethyl-amine (from Step 1) is dissolved in 25 ml water, cooled in an ice bath, and 3.64 g trimethylsilyl cyanide is added at such a rate, that the internal temperature does not exceed 10° C. Then the mixture is stirred at ambient temperature for 18 hours, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated, to give 2.1 g 1-Dimethylamino-4-(N′,N′-dimethyl-hydrazino)-piperidine-4-carbonitrile. 1H-NMR (CDCl3): 2.74 ppm (m, 2H), 2.50 ppm (m, 2H), 2.40 ppm (s, 6H), 2.35 ppm (s, broad, 1H), 2.24 ppm (s, 6H), 1.95 ppm (m, 2H), 1.60 ppm (m, 2H).
Reaction SMILES: [C@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C2C=C(CCO)C=CC=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].CC(OI1(OC(C)=O)(OC(C)=O)O[C:39](=O)[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]1=2)=O.C[CH2:51][O:52]CC>ClCCl>[C@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:38]=2[CH2:39][CH:51]=[O:52])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCOCC
Reactant: OCCc1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1
Solvent: ClCCl
Product: O=CCc1ccccc1-c1ccccc1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 2-(3-(2-α-D-mannopyranosyloxyphenyl)phenyl)ethanol (1.12 g, 2.46 mmol) in dichloromethane (15 ml) was added slowly to a suspension of Dess-Martin periodinane (4.95 g, 11.7 mmol) in dry dichloromethane (5 ml), and the reaction was stirred at room temperature overnight. The mixture was then diluted with ether and filtered; the filtrate was washed twice with saturated sodium bicarbonate solution and once with brine, then dried with magnesium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (4:1 hexane:ethyl acetate) to afford 2-(2-α-D-mannopyranosyloxyphenyl)phenylethanal (0.63 g, 57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:2]=1.O.NN.[OH-].[K+]>C(O)CO.O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:13]1
Reactant: O=C(CCCN1CCN(c2ccccn2)CC1)c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1ccc(N2CCN(CCCCc3cccnc3)CC2)nc1
Yield: 40.2 %

Procedure:
A solution of 1-(3-pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-1-butanone (Example 2) (5.2 g, 0.0168 mol), hydrazine hydrate (1.9 g, 0.0603 mol), and potassium hydroxide (3 g, 0.0538 mol) in ethylene glycol (100 mL) is refluxed 12 hours removing the water formed with a Dean-Stark trap. The cooled reaction mixture is diluted with water (100 mL) and extracted with dichloromethane. The organic layer is dried (sodium sulfate) and the solvent evaporate in vacuo. The resulting residue is crystallized from 2-propanol and diethyl ether to give 2 g of 1-(2-pyridinyl)-4-[4-(3-pyridinyl)butyl]piperazine as a white solid; mp 54-64° C.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:17])=[O:16])[N:11]=[C:10]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:32][C:26]1[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][S:23][C:10]1[N:11]=[C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2nccs2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2nccs2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-thiazolylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product from step ii) (0.11 g) in THF (3 mL) was added lithium borohydride (2M solution in THF, 0.23 mL) and the mixture was mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C., quenched with 0.5M HCl solution and the aqueous was extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white solid. Yield: 15 mg
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:32][C:29]([CH2:33]O)([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:32][C:29]([CH2:33][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2
Reactant: OCC12CCCN(CC1)C2
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCC12CCCN(CC1)C2)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of indole-3-carboxylic acid (1.45 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.53 g, 9.4 mmol), stirred for one hour, and degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.42 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (9.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The acid 1,1'-carbonyldiimidazole adduct (suspension) was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 5% methanol/methylene chloride). The concentrated filtrate was recrystallized from acetonitrile (2 crops) to afford 1.34 g (52%) of colorless solid; mp 183.5°-185.0° C.