Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24])[CH2:27][CH3:28]
Reactant: CCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Propyl chloroformate (31 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(propoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:23]#[N:24].[K+].[Na+].[Cl-].C(=O)([O-])O.[Na+]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][C:23]#[N:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#CCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 27.1 %

Procedure:
1.59 g of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-chloroacetamide was dissolved in 9 ml of dimethylformamide in accordance with preparation method A, and 637 mg of potassium cyanide was added thereto, followed by stirring at external temperature of 90° C. for 1.5 hours. After the reaction solution was cooled down, saturated NaCl solution was added and extraction was carried out with ethyl acetate and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The thus obtained residue was dissolved in benzene, and then hydrochloric acid-ether solution was added thereto to obtain a deposited oily substance by an inclination method. Then, aqueous saturated sodium hydrogencarbonate solution was added to the thus obtained oily substance and extracted again by ethyl, dried over magnesium sulfate, distilled under reduced pressure to obtain a brown oily substance. This was subjected to silica gel column chromatography (solvent; chloroform:methanol=7:1). 418 mg of light brown oily N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-cyanoacetamide was obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>CN(C)C=O>[I:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:6]=2[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cc(I)c2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A solution of 7-iodo-5-nitro-1,3-benzoxazol-2(3H)-one (1.6 g, 5.3 mmol) in N,N-dimethylformamide (11 mL) at 0° C. was treated with potassium carbonate (1.2 g, 8.4 mmol) followed by methyl bromoacetate (0.75 mL, 7.9 mmol) and stirred at 20° C. for 2 h. The reaction mixture was added dropwise to a solution of 1M HCl (100 mL) at 0° C. and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude solid. This material was washed with cold methanol to give the desired product (1.6 g, 79%) as a solid. LCMS for C10H81N2O6 (M+H)+: m/z=378.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and 4-chlorobenzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.91 (s, 2H), 7.78 (d, 2H), 7.49 (d, 2H), 7.44 (d, 2H), 7.23 (m, 2H), 7.14 (m, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.36 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 536 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][C:22]2[C:24]([CH3:38])=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]=2[O:20]1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:31]([O:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]2[O:20][CH:19]([CH2:18][CH2:17][NH:16][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH2:23][C:22]=2[C:24]=1[CH3:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN)O2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NCCC2Cc3c(C)c(OCc4ccccc4)c(C)c(C)c3O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.86 g of 3,4,5-trimethoxybenzoyl chloride in 35 ml of chloroform is slowly added to a 3.85 g solution of 2-(RS)-(2-aminoethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-benzofurane in 35 ml of chloroform and 2.0 ml of triethylamine. After stirring for one hour at room temperature, 1 M hydrochloric acid is added and the organic phase is separated and washed in a sodium bicarbonate solution, dried and evaporated. 4.42 g of--a white solid are obtained that is purified by crystallization from ethanol/ethyl acetate. m.p. 171°-173° C. IR(KBr): 3271 (νN--H), 1684, 1545 cm-1 (νCONH); 1H-NMR (CDCl3): δ7.4-7.2 (5H,m), 7.0 (2H,s), 6.8 (1H,t), 5.1-4.7 (1H,m), 4.7 (2H,s), 3.8 (9H,s), 3.8-3.4 (2H,m), 3.2-2.7 (2H,m), 2.2 (6H,s), 2.1 (3H,s), 2.1-1.8 (2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Oc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloropyridin-4-yl)oxy)-4-nitrothiophene-2-carboxylic acid (70 mg, 0.21 mmol) from above and 1-methylpiperidin-4-amine (28.5 mg, 0.25 mmol). The title compound was obtained as a solid (35.0 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (1H, m), 8.62 (2H, m), 8.57 (1H, s), 3.88 (1H, m), 3.12 (2H, m), 2.60 (2H, m), 2.50 (3H, s), 1.93 (2H, m), 1.77 (2H, m). MS m/z: 431.05, 433.14 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23](O)=[O:24])([O-:20])=[O:19].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH:15][C:12]1[CH:13]=[N:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[N:10][CH:11]=1)=[O:24])([O-:20])=[O:19]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To 2-(3-(trifluoromethyl)phenyl)pyrimidin-5-amine (750 mg, 3.14 mmol, 1.00 equiv) in dichloromethane (50 mL) was added 2-nitro-5-(piperidin-1-yl)benzoic acid (1.18 g, 4.72 mmol, 1.50 equiv), EDC.HCl (1.2 g, 6.28 mmol, 2.00 equiv) and 4-dimethylaminopyridine (770 mg, 6.31 mmol, 2.00 equiv) and the resulting solution was stirred for 48 h at room temperature. The reaction was diluted with 25 mL of water and then extracted with 2×25 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, concentrated, and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30-1:5) to give 0.4 g (27%) of product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:29][CH2:28]1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[S:20][C:19]([C:21]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH2:39][CH2:38]3)=[O:23])=[N:18][N:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.26 mmol), 1-(1-methyl-piperidin-4-ylmethyl)-piperazine (61 mg, 0.31 mmol), trimethylaluminium (2 M in toluene, 0.28 mL) and THF (10 mL).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20](=[S:22])[NH:19][N:18]=1.[OH-].[Na+].I[CH3:26]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][C:20]([S:22][CH3:26])=[N:19][N:18]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)o2)c1Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccccc2Nc2c(Cl)ccc(C)c2Cl)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
To a room temperature suspension of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazole-2(3H)-thione (1.706 g, 4.85 mmoles) in 70 ml of methanol is added dropwise 5.0 ml of 1.0N sodium hydroxide. The clear pale yellow solution is stirred at room temperature for 10 minutes. Iodomethane (320.0 μl, 5.13 mmoles) is added dropwise, and stirring is continued for six hours. The white solid is collected by filtration and dried in vacuo overnight at 60° C. to provide 1.530 g (86%) of 2,6-dichloro-3-methyl-N-[2-[5-(methylthio)-1,3,4-oxadiazol-2-yl]phenyl]benzenamine, mp 170°-171° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1.CN(C)C=O.O1CCOCC1>C(N(CC)CC)C>[F:18][C:17]1[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:16]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(C(F)(F)F)cnc1N1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.76 g), 2-bromo-3-fluoro-5-(trifluoromethyl)-pyridine (2.95 g), N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (5.07 ml) are heated in a sealed vessel at 120° C. with stirring for 1 h. After cooling the mixture is concentrated and partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer is extracted with ethyl acetate (100 mL) and the combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 21): tR=7.59 min; Mass spectrum (APCI): m/z=307 [M+H]+.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]1([CH:12]2[O:19][CH2:18][C@H:17]3[C@:15]([CH2:20][OH:21])([CH2:16]3)[CH2:14][O:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.O>ClCCl>[CH3:4][S:1]([O:21][CH2:20][C@:15]12[CH2:16][C@H:17]1[CH2:18][O:19][CH:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:13][CH2:14]2)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Reaction time: 1 h

Procedure:
In a reactor, a solution of mesyl chloride (280 g, 2.4 mol) in dichloromethane (2 L) was added to a mixture of [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol (450 g, 2.0 mol) and triethylamine (310 g, 3.1 mol) in dichloromethane (4.7 L). A maximum internal temperature of 27° C. was observed. The mixture was stirred for 1 hour. Water (4.5 L) was added, phases were separated and the aqueous phase was extracted with dichloromethane (2.3 L). The combined organic phases were washed with water (2.3 L) and subsequently concentrated under reduced pressure yielding off-white solid product. This material was used as such in the next reaction step without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][O:17][CH3:18]>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCBr
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 908.6 %

Procedure:
Prepared from tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and 1-bromo-2-methoxyethane (0.695 g, 5.0 mmol) according to the procedure described for Example 138, Step A. The product was obtained as a waxy solid (11.10 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.Cl.[Cl:30][C:31]1[C:32]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([N:42]2[CH2:43][CH2:44][CH:39]([O:38][C:32]3[C:31]([Cl:30])=[CH:36][C:35]([Cl:37])=[CH:34][N:33]=3)[CH2:40][CH2:41]2)=[O:20])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: Clc1cnc(OC2CCNCC2)c(Cl)c1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCC(Oc2ncc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
To a mixture of {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenoyl]amino}-3-(2-pyridyl)propanoyl]amino}acetic acid (0.19 g), 3,5-dichloro-2-(4-piperidinyloxy)pyridine dihydrochloride (0.16 g), 1-hydroxybenzotriazole (0.084 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) in N,N-dimethylformamide (2.5 ml) was added dropwise N,N-diisopropylethylamine (0.27 ml) at 8° C. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (231 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1nc(-c2cccc(CO)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A mixture of [6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]methyl acetate (0.30 g, 1.00 mmol), potassium carbonate (0.004 g, 0.03 mmol) and methanol (30 ml) was stirred under nitrogen atmosphere at room temperature for 2 hrs. The reaction mixture was concentrated, dissolved in hot ethanol (10 ml) and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol to give the titled compound (0.19 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:34])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25](OCC)[O:26]CC)=[C:19]([O:32][CH3:33])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(O)(=O)C>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:34])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=[O:26])=[C:19]([O:32][CH3:33])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(CCc1ccc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)cc1OC)OCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCC=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-[4-(3,3-diethoxy-propyl)-3-methoxy-phenyl]-5H-thiazolo[5,4-c]pyridin-4-one (180 mg, 0.36 mmol) in THF (2.0 mL) and water (1.0 mL) then add glacial acetic acid (0.6 mL). Stir the solution at 45° C. overnight. Dilute the solution with EtOAc (50 mL), wash with saturated NaHCO3 (20 mL), then dry, filter and concentrate the solution. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 80% EtOAc/hexanes, to give the title compound (94 mg, 61%). MS (ES+) 425.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 9.83 (s, 1H), 8.03 (d, 2H, J=8.3 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 7.26 (m, 1H), 6.99-6.89 (m, 3H), 3.84 (s, 3H), 2.99 (t, 2H, J=7.3 Hz), 2.77 (t, 2H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C.O>C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:4]([CH:3]=1)[CH:23]=[O:24]
Reactant: CC1(C)COC(c2ccc(Cl)cc2)N1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)COC(c2ccc(Cl)cc2C=O)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold solution of 2-(4-chloro-phenyl)-4,4-dimethyl-oxazolidine (17.2 g, 82 mmol) in ethyl ether (100 mL) and hexane (100 mL) at −30° C. was added n-BuLi (1.6 M in hexane, 67 mL, 107 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h, then cooled to −20° C. To the mixture was added DMF (12.6 mL), and the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into water (200 mL), extracted with ethyl ether for 3 times. The organic layers were combined, washed with water, dried over anhydrous Na2SO4, concentrated in vacuo to give the title product (13 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](I)=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:38])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(I)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (87 mg, 130 μmol, Eq: 1.00) was combined with DMF (3.48 ml) and water (174 μl). Potassium carbonate (35.9 mg, 260 μmol, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (3.48 mg, 15.5 μmol, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 70° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[N:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#CCc1cc2ccccc2cn1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-isoquinoline was synthesized (79%) from isoquinolin-3-yl-acetonitrile (234, 1.22 g, 7.26 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.64 g, 7.26 mmol) and NaH (Aldrich, 640 mg, 60%, 16.0 mmol) in a similar manner in two steps as described in Example 222. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.38 (s, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.57 (s, 1H), 4.68 (s, 2H). MS (EI): m/z 333 (M+H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6](=[O:30])[C@@H:7]1[CH2:11][C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][N:8]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CN(C)C=O>[CH3:4][O:5][C:6](=[O:30])[C@@H:7]1[CH2:11][C@@H:10]([C:1]#[N:2])[CH2:9][N:8]1[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: [C-]#N
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
Sodium cyanide (245 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-p-toluenesulfonyloxy-L-proline methyl ester (Compound D101 (K), 1.00 g) in N,N-dimethylformamide (10 mL)-water (22 mL). After stirring at 65° C. for 16 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:toluene=1:20, v/v) to give the title compound (197 mg): 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.33-2.52 (m, 2H), 3.25 (m, 1H), 3.69 (m, 1H), 3.75 (s, 3H), 3.90 (m, 1H), and 4.37-4.49 (m, 1H).