Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]=1
Reactant: Oc1ccc(Cl)nn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cl)ccc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
To a solution of 6-chloropyridazin-3-ol (0.5 g, 3.83 mmol, WO2011015629) in DMF (5 mL) was added potassium carbonate (1.059 g, 7.66 mmol, Rankem) followed by ethyl 2-bromoacetate (0.960 g, 5.75 mmol, Spectrochem). The reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with water (2 mL) and the product was extracted with EtOAc (3×20 mL). Combined organic layers were washed successively with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and evaporated under vacuum to afford ethyl 2-(3-chloro-6-oxopyridazin-1(6H)-yl)acetate 0.5 g (60.3%) as pale yellow solids. 1H NMR (400 MHz, CDCl3): δ 7.266-7.236 (d, J=12 Hz, 1H), 6.965-6.945 (d, J=7.6 Hz, 1H) 4.819 (s, 2H) 4.273-4.230 (m, 2H) 1.309-1.279 (m, 3H); MS m/z=217.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:22])[C:5](=O)[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[C-:23]#[N:24].[K+]>C(O)(C)C.O>[C:23]([CH2:2][C:3]1[N:4]([CH3:22])[CH2:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:24]
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(c1)C(c1ccccc1)=C(CC#N)N(C)C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (6.82 g, 19.0 mmol) in 100 mL of isopropanol was added a solution of potassium cyanide (2.48 g, 38.1 mmol) in 10 mL of water. The mixture was heated at 80° C. After one hour, another portion of potassium cyanide solution (300 mg in 5 mL of water) was added, and the reaction stirred for an additional hour. The solution was cooled to room temperature, and partitioned between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude solid material was triturated with EtOAc/ether to provide the titled product (5.01 g, 86% yield). HRMS (ES) exact mass calculated for C19H16N2O2 (M+H+): 305.1285. Found 305.1269.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14](Br)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:17])[CH2:4][CH2:3]2.C[Li].[CH2:20](OCC)C.C([Li])(C)(C)C.CCCCC.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=[O:39]>C1COCC1>[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[C:38]([C:14]1[CH:13]=[CH:12][C:11]2[C@:2]3([CH3:1])[C@@H:7]([CH2:8][CH2:9][C:10]=2[CH:15]=1)[N:6]([CH3:20])[C:5](=[O:17])[CH2:4][CH2:3]3)=[O:39]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Reactant: CCOCC
Reactant: O=Cc1ccccc1Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)c4ccccc4Cl)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a solution of (4aR)-(10bR)-10b-methyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one in 50 mL of THF at -78° under an atmosphere of nitrogen was added 2.25 mL of a 1.4M solution of methyllithium in diethyl ether (3.15 mmol). After 10 min, 3.34 mL of a 1.7M solution of t-butyllithium in pentane (5.68 mmol) was added. The reaction mixture was stirred for 10 min before the addition of 2-chlorobenzaldehyde (870 mL, 7.72 mmol) as a single aliquot. The reaction was warmed to room temperature and stirred for 2 h before partitioning between ethyl acetate and 1N hydrochloric acid. The organic layer was dried, filtered and evaporated under reduced pressure to afford 1.7 g of crude product. The material was purified on a Chromatotron (4 mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform) to give 435.5 mg of desired product (47% yield): mp 105°-115°; FDMS: m/e=355, 357.
Reaction SMILES: O.[C:2]([O-])(=[O:4])C.[NH4+].C=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:19]([C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])[CH:2]=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 200 ml of glacial acetic acid, and 61.7 g (0.8 mole) of ammonium acetate. To the stirred mixture there were slowly added 97 g of 37% formalin (1.2 moles of formaldehyde) and 20.6 g (0.1 mole) of 2,6-ditert.-butylphenol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (107°-9°) for 6 hours. After cooling to ambient temperature, the mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 15.8 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 184°-86° (67.5%).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:39][CH3:40].[CH3:41]C(C)CC(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:41])[C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[CH:38]=[CH:37][C:25]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH2:34]4)=[O:27])=[CH:24][C:23]=2[O:39][CH3:40])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CC(C)CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)c(OC)c2)CC1
Temperature: 160 °C

Procedure:
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 115 mg, 0.37 mmol) and 4-amino-N-(1-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 104 mg, 0.37 mmol) were dissolved 4-methyl-2-pentanol (3 mL). p-Toluenesulphonic acid monohydrate (142 mg, 0.74 mmol) was added and mixture heated by microwave irradiation at 160° C. for 1 hour.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+].[N+](C1C=CC=C2C=1CCC2=O)([O-])=O>OS(O)(=O)=O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=C1CCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
A solution of concentrated H2SO4 at 0° C. was treated with 1-indanone (6.00 g, 45.4 mmol) then treated dropwise with KNO3 (5.00 g, 49.94 mmol) in concentrated H2SO4 while maintaining the internal temperature at no more than 15° C. The reaction was stirred for 1 hour after the addition was complete, then poured onto ice. The resulting solids were collected by filtration, washed with water, and dried under vacuum to give a 4:1 mixture of 6-nitro- and 4-nitro-1-indanone (5.04 g, 63%). MS (ESI(+) m/e 178 (M+H)+, 195 (M+NH4)+; MS (ESI(−)) m/e 176 (M−H)−; 1H NMR (300 MHz, DMSO-d6, 6-nitro-1-indanone) δ 8.49 (dd, 1H), 8.29 (d, 1H), 7.87 (d, 1H), 3.25 (m, 2H), 2.78 (m, 2H); 1H NMR (300 MHz, DMSO-d6), 4-nitro-1-indanone) δ 8.51 (dd, 1H), 8.07 (dd, 1H), 7.74 (t, 1H), 3.53 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: Cl.[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].[CH3:20][S:21]([OH:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[SH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: SC1CNC1
Reactant: S=C=NCCCl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: SC1CN(C2=NCCS2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 63.3 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 10 dissolved in 1.0 ml of dried tetrahydrofuran, there was added 0.07 ml of triethylamine in the stream of nitrogen at a room temperature, and the resulting solution was stirred for 30 minutes. To this solution, there was added dropwise a solution of 70.3 mg of 2-chloroethylisothiocyanate dissolved in dried tetrahydrofuran, and the resulting solution was further stirred for one hour. After the reaction liquid was cooled to 0° C., 0.04 ml of methanesulfonic acid was added dropwise, and the resulting solution was stirred for 30 minutes, and, then, the solvent was evaporated in a vacuum. To the obtained residue, there was added 1.0 ml of dried methanol, and the resulting solution was subjected to heating and reflux for one hour, and, then, the solvent was evaporated in a vacuum. The obtained residue was separated and purified by thin-layer chromatography, and, thus, there was obtained 53.4 mg (yield: 39.2%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine methanesulfonate (13) in the form of colorless oily matter.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17]>>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(c2ccccc2)CC(=O)NC1=O
Product: CCCc1c(OCCCN2C(=O)CC(C)(c3ccccc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-Methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione was prepared as for Example 10 from 3-methyl-3-phenylpyrrolidine-2,5-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:36]4[CH:35]=[CH:32][CH:31]=[C:30]([O:29][CH:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:37]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCC(Oc2cccc(CN)c2)CC1
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.310 mmol), 3-(1-methyl-piperidin-4-yloxy)-benzylamine (0.109 g, 0.370 mmol) and phenol (1.0 g) were stirred at 130° C. for 2 hours. The reaction mixture was allowed to cool to r.t. and the product was partially purified by flash chromatography using a gradient elution with n-heptane against MeOH/TEA. The fractions containing the title product were concentrated in vacuo and purified further by washing with MeOH to give the title compound. Yield: 0.052 g (36%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.61 (d, 2H, J=8.52 Hz), 7.45 (s, 1H), 7.41 (d, 2H, J=8.52 Hz), 7.24 (m, 1H), 6.89 (m, 2H), 6.83 (d, 1H, J=9.02 Hz), 5.16 (s, 2H), 4.29 (bs, 1H), 2.65 (bs, 2H), 2.21-2.31 (m, 5H), 1.95 (m, 2H), 1.79 (m, 2H). MS (ESI+) 465.93 (M+1H+).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C1C=CN=CC=1)C.C(#N)C>[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[CH2:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])(=[O:29])=[O:30]
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(S(=O)(=O)NS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Yield: 64.7 %

Procedure:
Using 55.0 g (0.3 mol) of p-styrenesulfonamide, 3.7 g (0.03 mol) of 4-(N,N-dimethylamino)pyridine, 82.0 g (0.81 mol) of triethylamine, 91.8 g (0.42 mol) of 2-mesitylenesulfonyl chloride, and 500 ml of acetonitrile, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 70.9 g of N-(2-mesitylenesulfonyl) -p-styrenesulfonamide was obtained (yield, 64.7%; light-yellow crystals; m.p., 146.5-147° C.).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([O:26][C:27](=[O:37])[CH:28]=[CH:29][C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[C:22]([O:26][C:27](=[O:37])[CH2:28][C@@H:29]([C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(N)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of (R)-(+)-N-benzyl-α-methylbenzylamine (4.0 g, 19 mmol) in 50 mL THF was gradually added n-butyllithium (11.3 mL, 2.5 M, 28.2 mmol) over 5 min. The mixture was stirred for 30 min at 0° C. and cooled to -78° C. A solution of 10-2 (2.0 g, 9.4 mmol) in 20 mL THF was gradually added. After stirring for 40 min at -78° C., it was treated with NH4Cl (sat.) at -78° C., warmed to room temperature and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After solvent evaporation, the residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:2) to afford the desired product 10-3 as an oil.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[NH2:6][CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>ClCCl>[Cl:5][S:1]([NH:6][CH2:7][CH2:8][P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(CCN)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCNS(=O)(=O)Cl)OCC
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sulfuryl dichloride (1.1 g, 8.15 mmol, 1.47 equiv) in dichloromethane (10 mL). This was followed by the addition of a solution of diethyl 2-aminoethylphosphonate (intermediate 1.9) (1.0 g, 5.52 mmol, 1.00 equiv) and triethylamine (800 mg, 7.92 mmol, 1.43 equiv) in dichloromethane (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of ice water. The organic layer was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.5 g (crude) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N+:18]([O-])=O)[CH2:8][CH2:7]1>C(O)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NC1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Platinum(IV) oxide (15 mg, 0.07 mmol) was added to a solution of 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (187 mg, 0.50 mmol) in glacial acetic acid (5 ml). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The reaction mixture was then filtered through a pad of celite. The filtrate was made basic with a 15% sodium hydroxide solution and the product was extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1-(3,4-dichlorobenzyl)-4-(2-aminocyclohexyl)-piperazine (119 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:45][C:42]3[CH:43]=[CH:44][C:39]([N:36]4[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]4)=[CH:40][N:41]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:25])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A solution of 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (110 mg, 0.30 mmol) and 4-(6-amino-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (310 mg, 1.1 mmol) in toluene was heated at 100° C. for 10 hours and then cooled to room temperature. Diethyl ether was added to the reaction mixture and the product precipitated. This precipitate was collected by filtration and dried to provide 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg, 29%). M++1: Calc'd. 578.3, Found 578.4.
Reaction SMILES: C([BH3-])#N.[Na+].[Si:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[CH:15][C:14]=1[CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([CH:33]=[N:34][OH:35])=[CH:31][CH:30]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].O1CCOCC1.Cl>CO.C1COCC1>[Si:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:15][C:14]=1[CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][OH:35])=[CH:31][CH:30]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccc(C=NO)cc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccc(CNO)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride and a sodium acetate aqueous solution were added to an ethanol solution of 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]benzaldehyde, followed by stirring at room temperature for 18 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde oxime. Sodium cyanoborohydride was added to a methanol-THF mixed solution of the resulting 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde oxime, and then a 4 M hydrogen chloride dioxane solution was dropwise added thereto, followed by stirring at room temperature for 1 hour to obtain N-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzyl)hydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17]C)=[O:16])[N:11]=[N:10]2)[C:5]([F:8])=[CH:6][CH:7]=1.O=C(C)CC(OC)=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[N:10]2)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nnn(-c2c(F)ccc(Cl)c2F)c1C
Agent: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(=O)O)nnn1-c1c(F)ccc(Cl)c1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
Methyl 1-(3-chloro-2,6-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate: The mixture of Intermediate 26A (1.16 g, 6.12 mmol), methyl 3-oxobutanoate (0.729 mL, 6.73 mmol), NaOMe (1.539 mL, 6.73 mmol), and MeOH (12 mL) in a microwave vial was stirred at 65° C. overnight. The reaction was concentrated and purified by silica gel chromatography to isolate the desired product (46 mg, 2%) as a yellow solid. MS(ESI) m/z: 287.8 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([CH3:41])=[CH:22][C:23]2[S:31][C:27]3([CH2:30][CH2:29][CH2:28]3)[C:26](=[O:32])[N:25]([CH2:33][CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C:24]=2[CH:40]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:3])[CH3:2].CO.[ClH:44].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:44].[CH:1]([N:4]([C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)[C:18]([C:20]1[C:21]([CH3:41])=[CH:22][C:23]2[S:31][C:27]3([CH2:28][CH2:29][CH2:30]3)[C:26](=[O:32])[N:25]([CH2:33][CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C:24]=2[CH:40]=1)=[O:19])([CH3:2])[CH3:3]
Reactant: CCC(=O)NCCN1C(=O)C2(CCC2)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCC(=O)NCCN1C(=O)C2(CCC2)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl}carbonyl)amino]piperidine-1-carboxylate (2.5 g) in chloroform (7 ml)-methanol (15 ml) was added a 4N hydrochloric acid/dioxane solution (21 ml), and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure to give the title compound (2.2 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:20]=2)=[N:11][CH:10]=1
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
5-Benzyloxy-2- (4-hydroxyphenyl) pyrimidine (2 g, 0.0072 moles, Example 30) was dissolved in 15 ml of N,N-dimethylformamide in a 50 ml flask and 0.2 g of dry sodium hydride was added. After stirring the mixture for 15 minutes, 1.39 g (0.0072 moles) of octylbromide was added and the mixture was heated to 100° C. for 2 hours. Upon cooling to room temperature, 15 ml of water was added. The resulting solid was collected by filtration and the solid was then slurried in boiling methanol, cooled to room temperature, and again collected by filtration. The solid was hydrogenated on a Parr Hydrogenator with catalytic 10% palladium on carbon in tetrahydrofuran under 413.7 kPa hydrogen pressure for about 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator to yield 1.62 g (75% yield) of 5-hydroxy-2-(4-(octyloxy)phenyl)pyrimidine.