Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CN(C)C=O.O1CCCC1>[CH2:19]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCBr
Reactant: CC1(CCc2ccccc2O)COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccccc1CCC1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a suspension of sodium hydride (90 mg) in dimethylformamide (1 ml), under ice-cooling, a solution of 4-(2-(2-hydroxyphenyl)ethyl)-4-methyl-2-oxazolidinone (0.50 g) in dimethylformamide (2 ml) was added and the mixture was stirred at room temperature for 2 hours. To the solution, a solution of heptyl bromide (0.47 g) in tetrahydrofuran (2 ml) was added and the mixture was stirred at the same temperature for 5.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane ethyl acetate=1:1) to give the subject compound (0.60 g).
Reaction SMILES: C1(NC2N=C(C3C=CC=CN=3)C=C(C3C=NC=C(C#CCN4CCN(C(C)C)CC4)C=3)C=2)CC1.Br[C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[C:46]([NH:48][CH:49]([CH3:51])[CH3:50])[N:45]=[C:44]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)[CH:43]=2)[CH:39]=[N:40][CH:41]=1.C(N1CCN(CC#C)CC1)(C)C.[C:70]([N:74]1[CH2:79][CH2:78][N:77]([CH2:80][C:81]#[CH:82])[CH2:76][CH2:75]1)([CH3:73])([CH3:72])[CH3:71]>>[C:70]([N:74]1[CH2:75][CH2:76][N:77]([CH2:80][C:81]#[C:82][C:36]2[CH:37]=[C:38]([C:42]3[CH:47]=[C:46]([NH:48][CH:49]([CH3:51])[CH3:50])[N:45]=[C:44]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=4)[CH:43]=3)[CH:39]=[N:40][CH:41]=2)[CH2:78][CH2:79]1)([CH3:73])([CH3:72])[CH3:71]
Reactant: C#CCN1CCN(C(C)(C)C)CC1
Reactant: CC(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: C#CCN1CCN(C(C)C)CC1
Agent: CC(C)N1CCN(CC#Cc2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)CC1
Product: CC(C)Nc1cc(-c2cncc(C#CCN3CCN(C(C)(C)C)CC3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to Cyclopropyl-{5″-[3-(4-isopropyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.127) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-isopropyl-amine (Example 2.46, step1) and by replacing 1-isopropyl-4-(prop-2-ynyl)piperazine (Intermediate D1) with 1-tert-Butyl-4-prop-2-ynyl-piperazine (Intermediate D2).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH3:20])[O:25][N:24]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1cc(C(=O)O)no1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)no1
Yield: 40.8 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 5-methylisoxazole-3-carboxylic acid (0.120 g, 0.946 mmol), HOBt (0.128 g, 0.946 mmol), DIPEA (0.165 ml, 0.946 mmol) and EDCI (0.181 g, 0.946 mmol) using DCM as solvent using the method of Example 34(d) affording 0.114 g of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (m, 3H), 2.48 (d, 3H), 2.56 (m, 3H), 4.29 (m, 1H), 4.43 (m, 1H), 4.59 (m, 1H), 6.41 (m, 1H), 6.44 (d, 1H), 7.44 (m, 1H), 7.50 (d, 1H), 7.56 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(C2CC=CO2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(Oc2cccc(NCc3cccc(C4CCCO4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
EX-608E) To a 1,2-dichloroethane (4 mL) solution of the aldehyde (0.19 g, 1.1 mmol) from EX-608D was added 3-phenoxyaniline (0.20 g, 1.1 mmol), NaB(OAc)3H (0.30 g, 1.4 mmol) and acetic acid (0.065 mL, 1.1 mmol). The cloudy solution was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 0.32 g (84%) of the desired N-(3-phenoxyphenyl)-[[3-(tetrahydro-2-furanyl)phenyl]methyl]amine product as a yellow oil which was used without further purification. The formation of the desired product was monitored by TLC.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[CH2:6]([O:11][C:9]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:10])[C:7]1[CH:8]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(O)CN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNC(=O)OCc1ccccc1
Yield: 142.1 %

Procedure:
To a round bottom flask equipped with Dean-Stark trap was added (1) (2 g, 7.4 mmol), phthalic anhydride (1.1 g, 7.4 mmol), triethylamine (0.1 mL) and toluene (50 mL). The reaction mixture was heated to reflux and water produced was collected. After refluxing for 2 hours, the solvent was removed. The residue was acidified using 1 N HCl, filtered and washed with water, dried to give 2.2 g of (2). 1H NMR (DMSO-d6, 400 MHz): δ 7.8 (m, 4H), 7.3 (m, 5H), 7.1 (d, 2H), 6.8 (d, 2H), 5.05 (m, 1H), 3.3 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>CO.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1ccc(N3CCOCC3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a light orange, homogeneous solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (0.1705 g, 0.302 mmol) in methanol (3.59 mL) and THF (10.78 mL) was added LiOH (0.029 g, 1.208 mmol) in water (5.44 μL, 0.302 mmol). After 1.5 hr, the reaction was concentrated in vacuo. Water was added to the residue and acidified to pH ˜6 with 1 N aqueous HCl. The insoluble material was filtered and dried over Drierite to give the desired product (0.14098 g, 0.263 mmol, 87% yield) as an orange solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 retool) was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 retool) and sodium triacetexyborohydride (13.8 g, 65 retool). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 retool) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) and the layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-aminooctane (14.6 g, 88%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])([CH3:19])[CH3:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)NS(C)(=O)=O
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)c(Cl)nc2ccccc12)NS(C)(=O)=O
Reaction time: 4 h
Yield: 89.6 %

Procedure:
N-{2-[(2-Chloro-3-nitroquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide (3.1 g, 8.3 mmol), 5% platinum on carbon (310 mg), and acetonitrile (40 mL) were added to a Parr vessel and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for four hours. An analysis by HPLC indicated the presence of starting material, and additional platinum on carbon (310 mg) was added. The reaction was shaken under hydrogen pressure overnight and filtered through a layer of CELITE filter agent. The filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to provide 2.55 g of N-{2-[(3-amino-2-chloroquinolin-4-yl)amino]-1,1-dimethylethyl}methanesulfonamide as a dark oil, which was used without purification.
Reaction SMILES: O.[C:2]([OH:12])(=[O:11])[C:3]1[NH:10][C:8](=[O:9])[NH:7][C:5](=[O:6])[CH:4]=1.N12CCCN=C1CCC[CH2:15][CH2:14]2.C(I)C.O>CN(C)C=O>[C:2]([O:12][CH2:14][CH3:15])(=[O:11])[C:3]1[NH:10][C:8](=[O:9])[NH:7][C:5](=[O:6])[CH:4]=1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 87400.6 %

Procedure:
Orotic acid monohydrate (53.19 g, 0.306 mmol) was added to a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (46.51 g, 0.306 mmol) in dimethylformamide (85 ml). After stirring for 5 min., ethyl iodide (57.14 g, 0.366 mmol) was added to the solution and the mixture was heated at 60° C. for 5 hrs. Water (1 L) was added, and the resulting precipitate was collected by filtration, washed with water, and dried to give ethyl orotate (49.25 g, 88%).
Reaction SMILES: Br[C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)[N:4]([CH3:17])[N:3]=1.[CH3:18][N:19]1CCCC1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]1[N:4]([CH3:17])[N:3]=[C:2]([C:18]#[N:19])[C:14]1=[CH:13]2
Reactant: CN1CCCC1
Reactant: COc1ccc2nc3c(cc2c1)c(Br)nn3C
Product: COc1ccc2nc3c(cc2c1)c(C#N)nn3C
Temperature: 0 °C

Procedure:
A mixture of 32.0 g 3-bromo-6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline (Example 32) and 20.2 g cuprous bromide in 220 ml N-methylpyrrolidine was stirred and heated at reflux for 3 hours. The reaction mixture was poured into ice-water, and the solid product was collected by filtration. The latter product was treated with dilute aqueous sodium cyanide and purified by extraction with ethyl acetate and chromatography to give 4.5 g 6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-carbonitrile, bright-yellow solid, m.p. 190°-191° C., when recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:8])=O.Cl.Cl.[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH2:27].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:27][C:6](=[O:8])[CH:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1F)Cc1ccccc1F
Yield: 71.8 %

Procedure:
In 30 ml of N,N-dimethylformamide were suspended 1.8 g of bis(2-fluorobenzyl)acetic acid and 1.9 g of L-histidine methyl ester dihydrochloride, and to the suspension were successively added 1.68 ml of diphenylphosphoryl azide and 2.9 ml of triethylamine with stirring under ice-cooling. The mixture was still stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1) to obtain 2.0 g of N- bis(2-fluorobenzyl)acetyl-L-histidine methyl ester having an Rf1 value of 0.76 as a white powder.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][N:32]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[C:12]([CH3:15])=[CH:13][S:14][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Yield: 35 %

Procedure:
A mixture of 9.3 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 6.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine, 10.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. THe reaction mixture was cooled and water was added. The layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4 parts (35%) of 6-[2-[4-[2-(4-fluorophenyl)1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 140° C. (compound 35).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:10]=C([N+]([O-])=O)[CH:8]=[CH:7][N+:6]=1[O-:14].O1CCC[CH2:16]1>>[CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N+:6]([O-:14])=[C:5]([CH3:10])[CH:4]=1
Reactant: CNC
Reactant: C1CCOC1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Product: Cc1cc(N(C)C)cc[n+]1[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of dimethylamine in tetrahydrofuran (2M, 20 ml) was added 2-methyl-4-nitropyridine N-oxide (3.08 g), and the mixture was stirred at 60° C. for 8 hours. The residue was evaporated under reduced pressure and purified by column chromatography (silica gel 75 g, 0 to 10% methanol in dichloromethane) to give 4-dimethylamino-2-methylpyridine N-oxide (1.76 g).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrCC([C:20]1[C:29]2[C:24](=[C:25]([Cl:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=O.C([O-])([O-])=O.[K+].[K+].[CH3:39][C:40](C)=[O:41]>>[ClH:32].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:39][C:40]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:25]=3[Cl:32])[CH:20]=2)=[O:41])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(C(=O)CBr)cccc2c1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2cc(C(=O)CN3CCN(Cc4ccccc4)CC3)ccc2c1Cl

Procedure:
A mixture of N-benzylpiperazine dihydrochloride (2 g, 9.4 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-1-yl) ethanone (3.54 g, 11.3 mmol) and K2CO3 (4.55 g, 33 mmol) in acetone (120 ml) was treated according to the general preparation 2 to obtain N1-benzyl-N4-(5-chloro-6-methoxy-2-naphthoylmethyl) piperazine dihydro-chloride (2.85 g). The above product (2.6 g, 30 mmol) was reduced with NaBH4 (2.22 g, 60 mmol) in methanol (150 ml) according to the general preparation 3 to obtain 10.2 g of the title compound as white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19].[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][N:36]([C:39](=[O:41])[NH2:40])[C:35]1=[O:42])=[O:30])([CH3:27])([CH3:26])[CH3:25].[K]>O1CCCC1.C(N(CC)CC)C>[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][N:36]([C:39]([NH:40][S:18]([NH:21][C:22]([N:14]2[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]2=[O:16])=[O:23])(=[O:20])=[O:19])=[O:41])[C:35]1=[O:42])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C(N)=O)C1=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN1CCN(C(=O)NS(=O)(=O)NC(=O)N2C[C@H](NC(=O)OCc3ccccc3)C2=O)C1=O
Temperature: -70 °C
Yield: 99.5 %

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2azetidinone (2 g) was suspended in 200 ml of dry tetrahydrofuran and cooled to -70° C. Chlorosulfonylisocyanate (1.4 g) dissolved in 7 ml of dry tetrahydrofuran was added with stirring. The temperature was allowed to rise to 0° C. and this temperature was maintained for 10 minutes. Afterwards it was cooled to -40° C., 1.2 g of triethylamine was dropped in and 2.9 g of 1-[2-[(t-butoxycarbonyl)amino]ethyl]-3-carbamoyl-2-oxoimidazolidine was added. This mixture was stirred at room temperature for 14 hours. Following the work-up procedure described in example 34A yielded 5.4 g of (S)-[1-[[[[[[3-[2-(t-butoxycarbonylamino)ethyl]-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3azetidinyl]carbamic acid, phenylmethyl ester, potassium salt.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].CN(C)C=O.[CH2:41]([NH2:46])[CH2:42][CH2:43][CH2:44][CH3:45]>O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:35])[C:23]([NH:46][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:24])[N:17]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)C(=O)OC
Reactant: CCCCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Yield: 74.4 %

Procedure:
0.65 g (1.1 mmol) of methyl 2(S)-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)propanoate, 12 ml of dimethylformamide and 1 ml (8.8 mmol) of pentylamine are heated at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 0.35 g (76%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}propanoate is obtained.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][C@H:5]1[OH:13])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([OH:13])[CH2:6]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)OCCN1CC[C@H](N=[N+]=[N-])[C@H](O)C1
Reaction time: 10 h

Procedure:
A solution of cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was treated at −20° C. dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) in dichloromethane (5 mL). The temperature was allowed to reach 0° C. and kept at 0° C. for 10 hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was codistilled with city DMF (10 mL) without beating. This crude preparation of the mesylate was used without further purification directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.[N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]=[S:28]>CS(C)=O.O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=2[F:25])[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[S:28])=[N:7][CH:6]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(C)n1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)c3cc(C)nn3C)c2)cn1
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of N-{5-[(6-aminopyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (860 mg, 2.51 mmol) in DMSO (5 mL) was added ethyl isothiocyanatoformate (428 mg, 3.27 mmol), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (1.16 g, 98%) as a yellow oil.