Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.Br[CH:37]1[CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:39]([N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)[CH:37]=[CH2:38]
Reactant: BrC1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 11.1 %

Procedure:
In a sealed tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) in DMF to give a brown solution. bromocyclopropane (76.9652 mg, 0.636 mmol) and potassium carbonate were added. The reaction mixture was heated at 80 degree for 16 h. The reaction mixture was then heated under microwave 100 degree for 2 h and 130 degree for 8 h. The reaction mixture was partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated using phase separator and concentrated. The crude product was purified by column (biotage, 25 g) eluted with ethyl acetate/cyclohexane to afford product (12 mg). 1H NMR (500 MHz, CDCl3) 7.17-7.23 (m, 8H), 7.07-7.10 (m, 2H), 5.77-5.84 (m, 1H), 5.18-5.24 (m, 2H), 4.51 (d, 2H), 2.2-2.5 (m, 4H), 1.9-2.0 (m, 1H), 1.69-1.79 (m, 1H), 1.1-1.35 (br, 9H). LCMS (Method A): RT=7.9 min, M+H+=512.17.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=O.[OH-].[Na+].Cl>O.C(O)C>[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8](=[N:2][OH:3])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NO
Reactant: O=C(c1cccc(F)c1)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C(c1cccc(F)c1)c1cccc(F)c1
Temperature: 20 °C
Yield: 96.7 %

Procedure:
3-3′-Difluorobenzophenone oxime may be prepared according to the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm3 of water is poured dropwise into a solution of 5.0 g of 3,3′-difluorobenzophenone in 10 cm3 of ethanol, and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under reflux for 10 minutes, is cooled to 20° C. and then acidified with 7.5 cm3 of 4 N hydrochloric acid. Once triturated, the oily precipitate obtained becomes a white solid which is filtered, washed with water and then dried at 35° C. under reduced pressure (2.7 kPa). 5.17 g of 3,3′-difluorobenzophenone oxime are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2
Temperature: 0 °C

Procedure:
2.7 g of 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 4.3 g of powdered potassium carbonate, 200 mg of potassium iodide and 90 ml of toluene, with 3.2 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated for 24 hours under reflux. Then the mixture is poured on to ice-water, diluted with benzene and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained 3-[2-[4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is recrystallised from acetone/petroleum ether. The maleate melts at 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16]N1C(=O)CCC1=O.O>O1CCCC1>[Br:13][C:11]1[CH:10]=[C:9]([CH:14]=[O:15])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:12]=1[Cl:16]
Reactant: O=Cc1cc(Br)cn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)c(Cl)n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(4-bromo-2-formyl-1H-pyrrol-1-yl)-pyridine in 30 ml of tetrahydrofuran was added 1.5 g of N-chlorosuccinimide. The resulting mixture was stirred at room temperature for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.5 g of 4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 0.33 h

Procedure:
Triethylamine (149 μL, 1.07 mmol, 10.00 equiv) and pivaloyl chloride (26 μL, 0.214 mmol, 2.00 equiv) were added sequentially to a solution of 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, 0.107 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated and the residue purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)-2-phenyl-2,5-dihydro-1H-pyrrole (10-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, 1H, J=8.8, 5.2 Hz), 7.33 (m, 4H), 7.26 (m, 1H), 7.05 (dd, 1H, J=9.2, 3.1 Hz), 6.99 (m, 1H), 6.20 (m, 1H), 5.98 (m, 1H), 5.00 (m, 2H), 1.28 (s, 9H). LRMS m/z (M+H) 358.0 found, 358.1 required.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]\[C:18]([OH:20])=O.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:21]/[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])=[CH:17]/[C:18]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:20]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)Nc2ccncc2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
A suspension of 13-cis-retinoic acid (0.10 g, 0.33 mmol), CH2Cl2 (5 mL), 4-aminopyridine (0.03 g, 0.33 mmol), and DCC (0.07 g, 0.33 mmol) was stirred at room temperature for 24 h. The mixture was filtered, concentrated, and purified by silica gel flash column chromatography to give the product as a yellow solid (0.07 g, 57%). EIMS m/z: 377 ([M]+), 375 ([M]−).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].CCN(C(C)C)C(C)C.C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[NH:1][C:24](=[O:25])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(O)c1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25.0 g (200 mmol) 2-amino-m-cresol and 70.4 mL (400 mmol) DIPEA were placed in 1.0 L DCM and cooled to 0° C. To this a solution of 38.0 g (227 mmol) CDI was added dropwise over 30 min. The mixture was stirred for 30 min at 0° C., then stirred overnight at RT. After evaporation of the reaction mixture i. vac. down to half the volume, the aqueous phase was washed with water (2×250 mL), 1M aqueous potassium hydrogen sulphate solution (1×250 mL) and again water (1×250 mL). The organic phase was evaporated down i. vac. The crude product left as a solid was triturated with a mixture of diethyl ether and PE, the precipitated solid was suction filtered, washed with PE and dried i. vac.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][S:15]([CH2:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=O.[I-].[Na+]>CC(C)=O>[CH3:14][S:15][CH2:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)CS(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)CSC
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
A solution of trifluoroacetic anhydride (1.68 g) in acetone (5 ml) was added to a stirred mixture of 1-methylsulphinylheptadecan-2-one (1.58 g) and sodium iodide (1.8 g) in acetone (10 ml) cooled in an ice bath. The mixture was stirred for a further 10 minutes and then evaporated. Water (50 ml) was added to the residue and the mixture was extracted with diethyl ether (2×40 ml). The ether extract was washed with a solution of sodium thiosulphate (3 g) in water (50 ml), dried over magnesium sulphate and evaporated to give 1-methylthioheptadecan-2-one (1.3 g), m.p. 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O1C=CN=C1C1C=C(N2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1CC(=O)N(c2cccc(-c3ncco3)c2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2cccc(Br)c2)c2ccc3ccccc3c2N1

Procedure:
The titled compound was prepared from 1-nitro-2-naphthyltriflate and 3-bromoaniline in a procedure similar to that of example 6 (1), example 1 (2) and (3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: CN(C)C1CCNC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(N(C)C)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and N,N-dimethylpyrrolidin-3-amine. LCMS (M+H)+=544.2/546.3.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].OS(O)(=O)=O>S([O-])([O-])(=O)=O.[Ag+2].O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[Br:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 3 h

Procedure:
Bromine (17.4 ml) was added dropwise over 40 min to a stirred mixture of 4-tert-butylnitrobenzene (59.5 g, 332 mmol), silver(II)sulfate (56.5 g, 181 mmol), H2SO4 (300 ml), and H2O (33 ml) at RT. The mixture was stirred for a further 3 h and then poured into 0.1 M Na2S2O5/H2O (1 L). The solid was filtered, washed with H2O, Et2O, and CH2Cl2. The filtrate layers were separated. The aqueous fraction was extracted with Et2O. The combined organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The yellow solid was triturated with hexanes to give a pale yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.[N:15]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([N:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:30][CH:29]=2)[CH2:32][CH2:33]1)=[O:14]
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Reactant: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCN(c3ccc(OCCCN4CCCCC4)cc3)CC2)c2cc(F)ccc21
Temperature: 120 °C
Yield: 15.2 %

Procedure:
A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid [WO 0071537 A1] (35 mg) and 1-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)piperazine (D11) (50 mg) in dichloromethane (1 ml) was treated with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (94.4 mg) and heated in a microwave (CEM™ Discover microwave) at 120° C. for 5 min. The reaction mixture was concentrated in vacuo and purified on a SCX cartridge (2 g) eluting with methanol-aqueous ammonia (10:1) followed by mass directed auto preparative HPLC to give the title compound (12 mg). LCMS RT=2.49 min, 478 (M+H)+
Reaction SMILES: [H][H].C([N:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.C>[Pd](Cl)Cl.C(O)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([N:14]2[CH2:13][CH2:12][O:11][NH:10][C:15]2=[O:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=C1N(Cc2ccccc2)OCCN1c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: Cl[Pd]Cl
Solvent: CC(=O)O
Product: O=C1NOCCN1c1ccc(Cl)c(Cl)c1
Yield: 96 %

Procedure:
Hydrogen was passed through a mixture of 3.37 g of 2-benzyl-4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine, 70 ml of acetic acid, 680 mg of animal charcoal and 0.6 ml of a 20% palladium chloride solution until absorption ceased and the mixture was filtered. The filter was washed with acetic acid and the filtrate was poured into ice water. The mixture was extracted with methylene chloride and the organic extracts were dried and evaporated to dryness. The crystalline product was taken up in isopropyl ether to obtain 2.37 g of 4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 152° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.Cl.[NH2:23][C:24]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[C:24]([CH2:31][CH3:32])([NH:23][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)=[O:17])[CH2:29][CH3:30]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1
Reactant: CCC(N)(CC)C(=O)OC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid (Example 230 b) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials, MS (EI): m/e=433.5 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4]1.[H][H]>CO.[Pd]>[ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH2:6][CH2:5][CH2:4]1
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N[C@H]1CCC[C@H]2CCCCN2C1=O
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To round bottom flask, 10% Pd/C (35 mg, 0.022 mmol) was added to a solution of (7S,10aR,Z)-7-amino-1,2,3,4,7,8-hexahydropyrido[1,2-a]azepin-6(10aH)-one hydrochloride (3.23 gm, 1.49 mmol) in MeOH (5 mL). A hydrogen atmosphere was introduced via balloon and the reaction mixture was stirred for 3 hr. The reaction mixture was diluted with MeOH and filtered. The filtrate was concentrated and the residue was dried under vacuum to give (7S,10aR)-7-aminooctahydropyrido[1,2-a]azepin-6(7H)-one hydrochloride (299 mg, 1.37 mmol, 92% yield) as a light yellow solid. Anal. Calcd. for C10H18N2O m/z 182.2. found: 183.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.C([Mg]Cl)(C)C.CO[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1.[Cl-].[NH4+]>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:3]=[N:4]1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (8.7 g, 27.1 mmol) in THF (75 mL) at 0° C. under argon was added isopropylmagnesium chloride as a 2 M solution in THF (27.1 mL, 54.3 mmol). The reaction was stirred for 1 h at 0° C. To it was added 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.7 mL, 40.7 mmol) and the mixture was stirred for an additional 1 h while allowing to warm to room temperature. It was then treated with saturated ammonium chloride (100 mL) solution and the product was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over sodium sulfate, and filtered. Crude material was concentrated under reduced pressure to afford 7.1 g (81%) of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a clear yellow oil. The material was taken on crude to the next step. MS m/z=323.2 [M+1]+. Calc'd for C16H27BN2O4: 322.2
Reaction SMILES: C(O)C.Cl[C:5]1[C:10]([Cl:11])=[N:9][CH:8]=[CH:7][N:6]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C(N(CC)CC)C>[Cl:11][C:10]1[C:5]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nccnc1Cl
Yield: 14.6 %

Procedure:
To an ethanol solution (10 mL) of 2,3-dichloropyrazine (1.0 g), glycine ethyl ester hydrochloride (940 mg) and triethylamine (1.9 mL) were added and the mixture was irradiated with microwave (150° C., 10 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium bicarbonate solution was added and the product was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (hexane: ethyl acetate=10:1) to give 212 mg (15% yield) of the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]4[N:15]=[CH:16][S:17][C:13]=4[CH:12]=3)[S:8][C:7]=2[CH:20]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[S:17]1[C:13]2[CH:12]=[C:11]([C:9]3[S:8][C:7]4[CH:20]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=4[C:10]=3[C:34]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:38][CH:37]=3)=[O:35])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: COc1ccc2cc(-c3ccc4ncsc4c3)sc2c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc3ncsc3c2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Example 18, Step 2 (63 mg, 0.21 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.38 mL, 0.25 mmol) in 1 mL of methylene chloride was added AlCl3 (212 mg, 1.6 mmol) and the reaction was stirred at room temperature for 3 hrs. When acylation was complete, to demethylate, ethanethiol (0.069 mL, 0.93 mmol) was added dropwise and the reaction stirred for a further 1.5 hrs. The reaction was cooled to 0° C. and quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with 10% MeOH/methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 2% MeOH/methylene chloride to 4% MeOH/methylene chloride as the gradient eluant to obtain the title product.