Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.Cl[C:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)/[C:29](=[N:38]/[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)(=[O:41])=[O:40])/[CH:28]=1.[SH:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>>[C:45]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:47][C:42]([S:39]([NH:38][C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]([OH:37])=[C:27]([S:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:28]=2)(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Reactant: CCOC(=O)CS
Agent: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O

Procedure:
5.2.60 Ethyl 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetate (14r) was prepared according to the procedure of procedure B for 10a except using (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b) and ethyl mercapto-acetate, which afforded the title compound 71.5 mg (85.5%) as an off-white solid, m.p.: 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I.CS[C:19]1[NH:20][CH2:21][CH2:22][N:23]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:15]=[C:19]2[NH:23][CH2:22][CH2:21][NH:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CSC1=NCCN1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C(N=C2NCCN2)c2ccccc2)cc1

Procedure:
A mixture of 3.37 g of α-(p-chlorophenyl)benzylamine and 4.54 g of 2-methylmercapto-2-imidazoline-hydroiodide was heated at 150°-160° C. for 20 minutes. After cooling, the reaction mixture was dissolved in methanol and the solution rendered basic with sodium hydroxide to give 2-(α-(p-chlorophenyl)benzyl)iminoimidazolidine having a melting point of 187°-189° C.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Mg+2].[C:6](=[O:9])([OH:8])[O-:7].[N+]([O-])([O-])=O.[Ce+3:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[C:1](=[O:2])([O-:4])[O-:3].[Ce+3:14].[C:6](=[O:7])([O-:9])[O-:8].[C:1](=[O:2])([O-:4])[O-:3].[Ce+3:14]
Reactant: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [Mg+2]
Product: O=C([O-])[O-]

Procedure:
Adding 5.6 m3 of the above magnesium bicarbonate solution (0.50 mol/L) into a reactor containing 6 m3 of cerium nitrate solution to react for 2 hours, and controlling the reaction temperature at 35° C. and the pH value of mother liquor at 5.7, cerium carbonate can be obtained. And then the cerium carbonate is filtered, washed, dried, and finally calcined at 650° C. for 5 hours to produce cerium dioxide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](CC1C=CC(OC)=CC=1)[CH:6]=[CH:5]2.C(OC([N:29]1[CH2:32][CH:31]([NH2:33])[CH2:30]1)=O)(C)(C)C.[ClH:34].C1C2C(=CC(NC3CCNCC3)=CC=2)C=CN=1>>[ClH:34].[NH:29]1[CH2:32][CH:31]([NH:33][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:30]1
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: Cl
Agent: c1cc2cc(NC3CCNCC3)ccc2cn1
Product: O=c1[nH]ccc2cc(NC3CNC3)ccc12

Procedure:
6-(Azetidin-3-ylamino)-2H-isoquinolin-1-one hydrochloride was prepared by Buchwald Reaction starting from 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (13) and 3-Amino-azetidine-1-carboxylic acid tert-butyl ester. BOC deprotection was performed as described for Isoquinolin-6-yl-piperidin-4-yl-amine (48).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OC(CCl)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-nitrophenol to give white title compound, m.p. 60°-63° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[NH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([NH:31][C:8]([C:7]2[C:2](=[O:1])[NH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][CH:6]=2)=[O:10])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: NC1CCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NC1CCC1)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C

Procedure:
600 mg (2.9 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid were dissolved in 5 ml of tetrahydrofuran, 658 mg (4.1 mmol) of N,N-carbonyldiimidazole were added and the mixture was heated initially at room temperature for 30 min and then under reflux for 30 min. A solution of 247 mg (3.5 mmol) of cyclobutylamine in 5 ml tetrahydrofuran was then added dropwise, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness and then taken up in ethyl acetate, washed with 1 N hydrochloric acid and water, dried and concentrated. Purification by column chromatography gave 160 mg (19% of theory) of a light-brown powder.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>CO>[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2ncccc2-c2ccccc2)CC1

Procedure:
Using General Procedure B: Reaction of 3-phenyl-2-pyridinecarboxaldehyde and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester in MeOH with NaBH4 gave {4-[(3-phenyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 0.96-1.25 (m, 4H), 1.40 (s, 9H), 1.81 (d, 2H, J=12.3 Hz), 1.92 (d, 2H, J=11.1 Hz), 2.29-2.39 (m, 1H), 2.56 (s, 1H), 3.36 (br s, 1H), 3.83 (s, 2H), 4.08-4.41 (br m, 1H), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.30-7.33 (m, 2H), 7.36-7.43 (m, 3H), 7.52 (dd, 1H, J=7.7, 1.5 Hz), 8.53 (dd, 1H, J=4.8, 1.8 Hz).
Reaction SMILES: C[Si](Cl)(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](/[CH:16]=[CH:17]/[C:18]2[CH:19]=[CH:20][C:21]([O:43][CH3:44])=[C:22]([O:24][P:25](=[O:42])([O:34]CC3C=CC=CC=3)[O:26]CC3C=CC=CC=3)[CH:23]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.[Na+:45].[I-].C[O-].[Na+]>CC#N.O>[P:25]([O-:42])([O-:34])([O:24][C:22]1[CH:23]=[C:18](/[CH:17]=[CH:16]/[C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:43][CH3:44])=[O:26].[Na+:45].[Na+:45]
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1OP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Trimethylsilylchloride (1.68 ml, 13.3 mmol) was added dropwise to a stirred solution of phosphoric acid dibenzyl ester 5-[(E)-2-(3-chloro-phenylcarbamoyl)-vinyl]-2-methoxy-phenyl ester (1.87 g, 3.32 mmol) and NaI (1.99 g, 13.3 mmol) in dry CH3CN (40 ml). The mixture was stirred for 1 h at RT and then diluted with water and extracted with AcOEt. The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude was triturated with AcOEt and Et2O, filtered and dissolved in EtOH (100 ml). NaOMe (714 mg, 13.3 mmol) was added and the resulting mixture was stirred for 2 hrs at RT. The solvent was evaporated to dryness and the residue was crystallized from water to give the title sodium (E)-5-(3-(3-chlorophenylamino)-3-oxoprop-1-enyl)-2-methoxyphenyl phosphate (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=O.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:33][C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: O=Cc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2cccs2)CC1
Yield: 40.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-aminohexyl)piperidin-4-yl)-methyl)benzamide (2.0 g), 2-thiophenecarboxaldehyde (0.62 g), sodium borohydride (0.42 g) and ethanol (40 ml) were reacted and treated in the same manner as in Example 121 to give 1.0 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-thienylmethylamino)hexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:32][CH2:33][F:34])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:33][F:34])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCF)C(=O)C1
Reaction time: 0.5 h

Procedure:
1-t-Butoxycarbonyl-3-oxopiperazine (21.6 g) is dissolved in dry DMF (500 ml) and potassium t-butoxide (24.2 g) is added. The mixture is stirred at 20-25° for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (J. Med. Chem., 23(9), 985-90 (1980), 25.9 g) is added and stirring continued at the same temperature for 24 hours. The solvent is removed and the residue partitioned between ethyl acetate and water. The organic phase is washed with water and concentrated. The residue is dissolved in isopropanol and diluted with iso-hexane forming a precipitate which is removed by filtration. The mixture is chromatoraphed (silica: eluting with a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane) to give 1-t-butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][C@@H:38]1[CH2:42][N:41]([CH2:43][C:44]23[CH2:53][CH:48]4[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]4)[CH2:45]2)[CH2:51]3)[C:40](=[O:54])[NH:39]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:44]12([CH2:43][N:41]3[CH2:42][C@@H:38]([CH2:37][OH:36])[NH:39][C:40]3=[O:54])[CH2:45][CH:46]3[CH2:47][CH:48]([CH2:49][CH:50]([CH2:52]3)[CH2:51]1)[CH2:53]2
Reactant: CC(C)(C)[Si](OC[C@@H]1CN(CC23CC4CC(CC(C4)C2)C3)C(=O)N1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N[C@H](CO)CN1CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
TBAF (400 mg, 1.6 mmol) was added to a solution of (S)-4-((tert-butyldiphenylsilyloxy)methyl)-1-(1-adamantylmethyl)imidazolidin-2-one (261 mg, 0.52 mmol) in anhydrous THF (5 mL) at 0° C. The reaction was stirred at rt overnight. The reaction solution was concentrated to give the residue, which was purified by preparative TLC (PE/EtOAc 1/1) to provide (S)-1-(1-adamantylmethyl)-4-(hydroxymethyl)imidazolidin-2-one (45 mg, 10%). 1H NMR: (CDCl3, 400 MHz): δ=1.54 (s, 6H), 1.62-1.73 (m, 6H), 1.98 (s, 3H), 2.77 (m, 2H), 3.35 (m, 1H), 3.55-3.75 (m, 3H), 3.82 (m, 1H); MS m/z=265
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([F:15])[CH:3]=1.[Li]C(C)(C)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>C1COCC1.CCCCC>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7]([NH:6][C:5]1[C:4]([F:15])=[CH:3][C:2]([Cl:1])=[CH:14][C:13]=1[C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])=[O:12]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
To a stirred, cooled (-50° C.) solution of 0.92 g (4.0 mmol) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7 M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with IN aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO4) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. 1H NMR(300 MHz, CDCl3) δ 8.68(s, 1H); 7.45-7.47(m, 1H); 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C13H13NO2ClF4 (M+H)+ : 326.0571, found: 326.0579.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1.C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:24][Br:32])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1-c1cccc(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(-c2cc(-c3nc4ccccc4o3)ccc2CBr)c1

Procedure:
A mixture of 5′-(1,3-benzoxazol-2-yl)-2′-methyl-1,1′-biphenyl-3-carbonitrile (229 mg, 0.74 mmol), n-bromosuccinimide (145 mg, 0.81 mmol), and benzoyl peroxide (9 mg, 0.037 mmol) in carbon tetrachloride (15 mL) was refluxed for 5 h. The solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 30 min: 0 to 20% EtOAc, 30 to 40 min: 50% EtOAc) to afford 5′-(1,3-benzoxazol-2-yl)-2′-(bromomethyl)-1,1′-biphenyl-3-carbonitrile as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Na].[CH2:13]([OH:18])[C:14]([F:17])([F:16])[F:15].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:18][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroehtoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): by 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (EI, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[OH:24])[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]5[OH:24])[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OC1CCCCC1Nc1ccc2ncc(-c3ccnc(Cl)c3)n2c1
Reactant: OB(O)c1ccoc1
Product: OC1CCCCC1Nc1ccc2ncc(-c3ccnc(-c4ccoc4)c3)n2c1

Procedure:
The title compound is prepared from (1SR,2SR)-2-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Intermediate K) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (6.91 g) and 2-aminobenzamide (11.8 g), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a white solid (6.2 g, 70% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.67 (d, J=4.03 Hz, 1 H), 7.17 (td, J=7.59, 1.10 Hz, 1 H), 7.47 (d, J=8.05 Hz, 2 H), 7.57 (td, J=7.87, 1.46 Hz, 1 H), 7.75 (d, J=4.03 Hz, 1 H), 7.78 (s, 1 H), 7.83 (dd, J=8.05, 1.46 Hz, 1 H), 7.98 (dt, J=8.69, 1.97 Hz, 2 H), 8.30 (s, 1 H), 8.44 (dd, J=8.33, 1.01 Hz, 1 H), 12.32 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:31]=[CH:30][C:8]([NH:9]/[C:10](=[C:19]2\[C:20](=[O:29])[NH:21][C:22]3[C:27]\2=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)/[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].N1C=CC=CC=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.[OH-].[Na+]>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:19]2\[C:20](=[O:29])[NH:21][C:22]3[C:27]\2=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)/[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])=[CH:15][CH:16]=2)=[CH:30][CH:31]=1)[CH3:1]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccc(CN)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccc(CNS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
100 mg of 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-aminomethyl-phenyl)-methylene]-6-chloro-2-indolinone (educt 14.0) are dissolved in 5 ml methylene chloride and at 0° C. 5 ml of pyridine and 45 μl of benzenesulphonylchloride are added. The mixture is stirred for 10 minutes at 0° C. and then for 2 hours at ambient temperature. After this time the solvent is eliminated, the residue is suspended in 1N sodium hydroxide solution, suction filtered and washed with a little water. The product is dried at 100° C.
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=O.[Na+:32].C(O)(=O)C>CO.[H][H].[Pd]>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:28])=[O:29])[C:24]1=[O:31])=[O:21].[Na+:32]
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCc1ccccc1CC(=O)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 77.9 %

Procedure:
In 35 ml of 30% methanol is dissolved 0.30 g of the above sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate, followed by addition of 0.68 ml of 6% acetic acid and 75 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temperature for 90 minutes. The catalyst is filtered off and the filtrate is purified on an Amberlite XAD-II column. The above procedure provides 0.167 g of sodium 3-[2-(2-aminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate.acetate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.ClC(OCC(C)C)=O.[NH3:47]>C(N(CC)CC)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:47])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (0.2 g) in a tetrahydrofuran (10 ml) were added isobutyl chloroformate (0.15 ml.) and triethylamine (0.2 ml) at 0° C. under N2. After being stirred for 30 minutes, NH3 (5 ml, 4M solution in methanol) was added to the mixture. After being stirred for 30 minutes, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N-NaOH and the organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue and 10% Pd/C (0.2 g) in methanol (20 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give and the obtained residue was purified by chromatography on silica gel to give 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}benzamide (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:37](O)[CH3:38].CC[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][O:12][CH2:37][CH3:38])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CO)n4ncnc(N)c34)sc12
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOCc1c(CN2CCNC(=O)C2)c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of Example 125 (100 mg, 221 μmol) in dichloromethane (10 ml) was treated with thionyl chloride (161 μl, 2.21 mmol), and the mixture was stirred at rt for 30 min. Ethanol was added, and the volatiles were evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), sodium ethylate (30 mg, 442 μmol) was added, and the mixture was stirred at rt for 1 h. The mixture was then directly separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were combined and alkalized by addition of sat. aq. sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated to yield 57 mg of the title compound (54% of th.).