Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:48][CH2:49][CH2:50][C@H:51]([OH:54])[CH2:52][OH:53]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([NH:48][CH2:49][CH2:50][C@H:51]([OH:54])[CH2:52][OH:53])=[O:39])[N:18]([C@H:17]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:16]([OH:15])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:19]43[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][CH2:24]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NCC[C@H](O)CO
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)NCC[C@H](O)CO)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Yield: 55 %

Procedure:
The compound (1.01 g, 1.51 mmol) obtained in Step 1 of Example 1 and (2S)-4-aminobutane-1,2-diol (WO2007/011162) (475 mg, 4.53 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 1 to give 644 mg (55%) of the title compound as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from ethyl 3-amino-2-benzoyl-6-fluoro-1H-indole-1-carboxylate (step 2) and methanesulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][Si:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromobenzyl alcohol (4.86 g, 26 mmol) in CH2Cl2 (80 mL) cooled to 0° C. was added Me3SiCl (3.12 g, 28.6 mmol), triethylamine (4.34 g, 31.2 mmol) and 4-N,N-dimethylaminopyridine (0.32 g, 2.6 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stirred whereupon reaction was determined by thin layer chromatography to be completed after 2 h. The solution was washed with 1N aqueous HCl (30 mL) H2O (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic phase was dried (MgSO4) and concentrated under vacuum to provide a brown oil, 6.67 g. Purification by column chromatography (80 g SiO2 eluted with 10% diethyl ether/hexane) afforded the product of Step A as a clear, yellow oil, 5.94 g, (88%); IR (neat): 2956, 2897, 1441, 1251 cm-1 ; 1H NMR (CDCl3); δ7.5 (dd, 2h), 7.3 (t,1H), 7.1 (t,1H), 4.7 (s,2H), 0.2 (s,9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>>[CH3:19][NH:20][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
Another illustration of derivatization of saturated ketone intermediates is the reductive amination to give amines. Thus, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with ammonium formate, zinc chloride and sodium cyanoborohydride to give 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer. Likewise, reaction of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one with methylamine and sodium cyanoborohydride provides 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. These amine derivatives can be used as a template for library formation by reacting them with a variety of acylating agents (e.g., acid chlorides, acid anhydrides, active esters, and carboxylic acids in the presence of coupling reagents) and isocyanates to produce 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes with amide and urea substituents in the 3-position of the 1-azabicyclo[2.2.2]octane, both of which classes are compounds of the present invention. Commercially unavailable isocyanates can be prepared in situ from corresponding amines and tiphosgene in the presence of triethylamine. Such derivtatives can be produced as single enantiomers, using the single enantiomers of 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as starting materials. For instance, the (2R,3R)- and (2S,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be produced by resolution of the cis 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, for example, using diastereomeric amides. Thus, when the cis amine is reacted with a chiral acid such as (S)—N-(tert-butoxycarbonyl)proline using a suitable coupling agent such as diphenylchlorophosphate, a pair of diastereomeric amides, separable by reverse phase chromatography, is produced. The separated proline amides can then be deprotected, for example, by treatment with trifluoroacetic acid (to remove the tert-butoxycarbonyl protecting group) and then the proline can be cleaved from the desired amine, for example, using Edman degradation conditions (i.e., phenylisothiocyanate, followed by trifluoroacetic acid).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:12]([CH2:15][C:16]#[N:17])=[N:13][CH:14]=1)([O-])=O>CC(=O)OCC>[NH2:6][C:9]1[CH:10]=[C:11]([C:18]([F:21])([F:19])[F:20])[C:12]([CH2:15][C:16]#[N:17])=[N:13][CH:14]=1
Reactant: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCc1ncc(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A suspension of tin(II) chloride dihydrate (58.6 mg, 0.260 mmol) in EA (60 mL) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (30 mg, 0.130 mmol) in EA (60 mL). The mixture was at 50° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16 mg, 0.080 mmol, 61.3% yield) was used in the next step without further purification. TLC (PE/EA=1:1, Rf=0.5): 1H NMR (400 MHz, CDCl3) δ: 8.19-8.27 (m, 1H), 7.22 (d, J=2.5 Hz, 1H), 3.97 (s, 2H); ES-LCMS m/z 202.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:13]([C:12]3[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[Cl:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1cc(Br)cnc1N
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (15 g, 79.78 mmol, 1.00 equiv), 2-chloro-5-nitrobenzoic acid (17.7 g, 87.81 mmol, 1.10 equiv) in PPA (200 mL) was stirred overnight at 130° C. and then quenched by the addition of 300 mL of H2O/ice. The pH value of the mixture was adjusted to 8 with sodium carbonate and the solids were collected by filtration, washed with water and dried in an oven under reduced pressure to give 36 g (crude) of 6-bromo-2-(2-chloro-5-nitrophenyl)-1H-imidazo[4,5-b]pyridine I-2a as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 62 %

Procedure:
To a stirred mixture of 2-amino-5-bromo-3-nitrobenzotrifluoride (261 mg, 0.949 mmol) in ethanol (4 mL) was added SnCl2 ·2 H2O (1.076 g, 4.745 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 with NaHCO3 and extracted by ethyl acetate (2×4 mL). The extract was dried over Mg2SO4 and evaporated to give 150 mg (64.6%) of 2,3-diamino-5-bromobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.503 (s, 2H); 3.898 (s, 2H); 6.987 (d, 1H, J=1.8 Hz); 7.123 (d, 1H, J=1.8 Hz).
Reaction SMILES: [OH-:1].[Na+].[O:3]1[C:14]2[C:10]3[NH:11][C:12](=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1.OO.Cl>O>[NH2:11][C:10]1[C:14]2[O:3][CH2:4][O:5][C:6]=2[CH:7]=[CH:8][C:9]=1[C:12]([OH:1])=[O:13]
Reactant: [OH-]
Reactant: O=C1Nc2c1ccc1c2OCO1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1OCO2
Yield: 64.4 %

Procedure:
To a solution of sodium hydroxide (4.6 g, 115 mmol) in water (35 mL) was added the Intermediate from Step C (2.35 g, 14.4 mmol). A solution of hydrogen peroxide (30%, 21 mL) was then added over 30 minutes. The reaction was neutralized to pH 7 by the addition of diluted hydrochloric acid (1N). The precipitate was collected and dried to afford the product 4-aminobenzo[d][1,3]dioxole-5-carboxylic acid (1.68 g, yield 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40-7.42 (d, 1H, J=8.4 Hz), 6.25-6.27 (d, 1H, J=8.4 Hz), 6.04 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:11]1[C:12](=[O:20])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:23]1=[O:24])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](NC(=O)c1ccccc1N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](c1ccccc1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (S)-(2-amino-benzoylamino)-phenyl-acetic acid methyl ester (330 mg, 1.16 mmol) in THF (30 mL) is added trichloromethyl chloroformate (115 mg, 0.58 mmol). The mixture is stirred at 90° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to give the (S)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl-acetic acid methyl ester (110 mg, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[S:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].O>C(O)CO>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:16]1[S:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Solvent: OCCO
Solvent: O
Product: CCOC(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Yield: 0.9 %

Procedure:
A solution of N-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (93.8 g, 0.293 mole) in ethylene glycol (500 ml) was refluxed for 45 minutes and cooled. A 10-ml aliquot was taken (0.005 mole) and added to water. The product was extracted into ethyl acetate twice and the combined organic layer was washed twice with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 0.8 g (53% yield) of solid. The solid was recrystallized from isopropyl alcohol/water to give 0.31 g of solid which was purified on a silica gel column using 1:1 methylene chloride/ethyl acetate as the eluting solvent. Evaporation of the solvent from the pure fraction and recrystallization of the resulting solid from isopropyl alcohol/water give title compound, mp 123°-125° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15](Cl)=[O:16])[CH:11]=1)(=[O:5])=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>N1C=CC=CC=1>[CH3:39][C:38]1[CH:37]=[CH:36][C:22]([C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[CH:21][C:20]=1[NH:19][C:15]([C:14]1[CH:13]=[N:12][N:10]2[CH:11]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:18])[CH3:1])[CH:7]=[CH:8][C:9]=12)=[O:16]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N
Reactant: CN(C)S(=O)(=O)c1ccc2c(C(=O)Cl)cnn2c1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cnn2cc(S(=O)(=O)N(C)C)ccc12

Procedure:
6-Dimethylsulfamoyl-pyrazolo[1,5-a]pyridine-3-carbonyl chloride (200 mg, 0.35 mmol) and 3-amino-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide are reacted in 2 ml dry pyridine at r.t. for 18 hrs. The solvent is removed under reduced pressure. The product is isolated by automated column chromatography and is dried at the high vacuum pump, yielding the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]2[O:26][C:27]([CH2:30]Cl)=[N:28][N:29]=2)[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([C:25]2[O:26][C:27]([CH2:30][N:4]3[C:5]4[C:10](=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH2:1][CH3:2])=[N:28][N:29]=2)[CH:22]=[N:21][CH:20]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: MS (ESI): m/z 476 (M−1).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 6 %

Procedure:
Using cyclohexyl{3-ethyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.90 g) synthesized in Example 39(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.75 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (85 mg, 6%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([O:49][C:50]1[CH:51]=[C:52]([C@@H:58]2[C@H:63]([NH2:64])[CH2:62][CH2:61][O:60][CH2:59]2)[CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH3:48]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:64][C@@H:63]2[CH2:62][CH2:61][O:60][CH2:59][C@@H:58]2[C:52]2[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:50]([O:49][CH2:47][CH3:48])[CH:51]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of terephthalic acid monomethyl ester, 5 mmol of ethyl di-isopropylamine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine the suspension is stirred over night at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid residue. M.p. 166-167.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>CC#N.CCN(CC)CC>[Cl:19][C:4]1[N:3]=[C:2]([NH:31][CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate (1.2 g, 3.9 mmol) and quinolin-6-ylmethanamine (616 mg, 3.9 mmol) in CH3CN (15 mL) and Et3N (1 mL) was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to afford the title compound (1.60 g). MS (m/z): 430 (M+1)+.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2sc(Br)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Slurry 2-amino-4-chlorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g, 0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes and then heat on a steam bath for an additional 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-4-chlorobenzothiazole.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:29]>>[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:38])[CH3:29]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CCc1ccccc1NC(N)=S
Product: CCc1ccccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-ethylphenyl)thiourea isolated as a white solid (0.104 g, 35%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.13 (s, 1H), 9.42 (s, 1H), 8.15-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.67-7.57 (m, 2H), 7.56-7.45 (m, 2H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.33-7.25 (m, 1H), 7.25-7.17 (m, 2H), 7.09-6.96 (m, 1H), 3.47 (q, J=6.5 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.58-2.51 (m, 2H), 1.11 (t, J=7.5 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 555 ([M+H]+), 553 ([M−H]−).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:20][CH2:19][CH2:18][N:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH2:21][CH2:22][OH:23]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccc(N(CCO)CCO)cc2)cc1
Temperature: 95 °C

Procedure:
A one liter three necked flask fitted with a mechanical stirrer, condenser and thermometer is charged with 21.7 g of 4-fluoro-4'-nitrobiphenyl, 31.0 g of diethanolamine, 13.8 g of potassium carbonate, 1.0 g of Aliquot 336, and 500 ml of dimethyl sulfoxide. The reaction mixture is heated at 95° C. for a period of three days, cooled, and poured into 4 litersof ice water. The crude solid product is filtered, washed with water, and dried.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C>[C:11]1([CH2:10][O:9][C:8]([NH:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][N:1]2[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(NC[C@H]1CCCN1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CCC[C@@H]1CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a mixture of phenylmethyl [(2R)-2-pyrrolidinylmethyl]carbamate (D109, 1.26 g, 5.38 mmol) and K2CO3 (1.48 g, 10.76 mmol) in acetonitrile (20 ml), cooled to 0° C., was added dropwise diethyl bromomalonate (1.08 ml, 6.46 mmol) in a 2-3 mins time. Then the reaction mixture was allowed to warm-up to r.t. and it was stirred at this temperature for 2.5 hrs. Further diethyl bromomalonate (1.08 ml, 1.6 mmol) was added and the reaction mixture was stirred for one more hour.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].[OH-].[Na+].C(Cl)(Cl)Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:35][C:33]4[CH:32]=[CH:31][C:22]([C:23](=[O:24])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:21]([OH:20])[CH:34]=4)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cc(C(=O)Cl)ccc3o2)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2nc3cc(C(=O)Oc4ccc(C(=O)c5ccccc5)c(O)c4)ccc3o2)cc1

Procedure:
A solution containing 5.42 g. (0.02 mole) of 1c, 4.28 g. (0.02 mole) of 2,4-dihydroxybenzophenone, and 0.8 g. (0.02 mole) of sodium hydroxide in 50 ml. of chloroform and 15 ml. of water was refluxed for 3 hours. After cooling, the layers were separated and the organic layer was concentrated to given 5.27 g. (59%) of 1e as a white crystalline solid: UV (CH2Cl2) λmax 306 nm (31,000), ε325 =18,500.