Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36]S(C3C=CC(C)=CC=3)(=O)=O)[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:33]2=[O:58])=[C:29](\[OH:31])/[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N12CCCCC1C=NCCC2.C(O)(=O)C>COCCOC.C(Cl)Cl>[C:13]1([CH:19]([O:26][C:27]([C:28]2[N:32]3[C:33](=[O:58])[C@@H:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@H:35]3[S:36][CH2:30][C:29]=2[OH:31])=[O:59])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 ml of bis-trimethylsilyl-acetamide (0.508 mmol) is added to a solution of 301 mg (0.462 mmol) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester in 3 ml of 1,2-dimethoxyethane under a nitrogen atmosphere, and the mixture is stirred for one hour at room temperature. The solution is completely concentrated by evaporation and the oily residue is dried for one hour under a high vacuum. The silylated crude product is taken up in 3 ml of dried 1,2-diethoxyethane and after cooling to 0° C. 0.075 ml (0.508 mmol) of 1,5-diazabicyclo [5.4.0]undec-5-ene is added. After 6 hours' reaction time at 0° C. under a nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture is diluted with methylene chloride. The methylene chloride solution is washed successively with dilute sulphuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride and the combined organic phases are dried with sodium sulphate, concentrated in vacuo and dried under a high vacuum. Crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained. An excess of a solution of diazomethane in ether is added to the solution of the crude product in chloroform at 0° C. and the mixture is left to stand for 5 minutes at 0° C. It is then concentrated completely and the residue is chromatographed on silica gel, as in Example 2. 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; Rf value=0.19 (silica gel; toluene/ethyl acetate, 3:1); melting point 120° C. (from ether), IR spectrum (in CHCl3); 3,310, 1,775, 1,710, 1,690 and 1,600 cm-1, is obtained.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:25][CH2:24]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:59][C@H:60]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:61][CH2:62][C:63](=[O:65])[OH:64]>C1COCC1.O>[C:69]([O:68][C:66](=[O:67])[CH:60]([NH:59][C:9](=[O:8])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:27][CH2:28]1)=[O:22])[CH2:61][CH2:62][C:63]([OH:64])=[O:65])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 83.6 %

Procedure:
To a solution of 2-({4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarbonyl}-amino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (5.0 g) in THF (100 ml) was added a solution of H-Glu-OtBu (1.36 g) in water (25 ml). After stirring over night the mixture was concentrated in vacuo. The residue was precipitated from water and filtered off and dried in vacuo to give the title compound (4.63 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])NCOC)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg+].[Br-].OS([O-])(=O)=O.[K+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g, 105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46 mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. The reaction was diluted with EtOAc, washed with H2O, 10% KHSO4(aq.), sat. NaHCO3, dried (MgSO4) and concentrated to give crude [2-(methoxymethyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3 as a yellow oil. TLC Rf=0.42 (silica, 20% EtOAc/hexanes). To a solution of this crude amide in THF (500 mL) at 0° C. was added CH3MgBr (100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10% KHSO4(aq.) was added, the mixture warmed to 25° C., and diluted with EtOAc. The organics were washed with sat. NaHCO3, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4 as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:43])[C:23]([CH3:42])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
Morpholine (0.025 g, 0.289 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.083 g, 0.434 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.050 g, 0.145 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.033 g, 0.0794 mmol, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH2:8][C:9](=O)[N:10]=[C:6]2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17].P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([Cl:20])[N:10]=[C:6]2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=CC(Cl)=C(N)N2CC(=O)N=C12
Product: CCOC(=O)c1cc(Cl)c(N)n2cc(Cl)nc12
Yield: 72 %

Procedure:
A solution of ethyl 5-Amino-6-chloro-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 24, Step 2, 0.50 g, 2.00 mmol) in phosphorus oxychloride (4 mL) was refluxed for 4 h. After cooling, the mixture was evaporated. The obtained residue was carefully treated with water and 25% aqueous ammonia. The formed solid was collected by filtration to give 385 mg (72%) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>COC(C)(C)C>[C:28]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=NC(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1
Reaction time: 0.33 h

Procedure:
9.32 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate are placed in 100 ml of tert.butyl methyl ether with 3.54 g of triethylamine. 4.92 g of benzoyl chloride are added dropwise within about 30 minutes while cooling with an ice bath. The mixture is then left to stir at 0°-5° C. for 20 minutes. The reaction mixture is poured into water and extracted twice with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The crude product is dissolved in ethyl acetate while warming and suction filtered over an about 3 cm deep layer of silica gel. The crystals obtained after evaporation of the filtrate are recrystallized from ethanol, and there is obtained ethyl N-benzoyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 116°-117° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 4-nitrobenzylamine (6.09 g, 40.0 mmol), 2-chloropyrimidine (4.82 g, 42.1 mmol), triethylamine (11.2 ml, 80.4 mmol) and ethanol (120 ml) was stirred at 110° C. for 24 hours, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate-THF. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give N-(4-nitrobenzyl)-N-(2-pyrimidinyl)amine (0.99 g, 4.3 mmol, 11%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][OH:39])=[CH:36][CH:35]=1.CC(C)([O-])C.[K+].CC(O)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26]([O:39][CH2:38][C:37]4[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2-c2cccnc2F)cc1)c1nc2ccccc2[nH]1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncccc2-c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
To a mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone (200 mg, 0.486 mmol) and 4-methoxybenzyl alcohol (0.905 mL, 7.29 mmol) in toluene in a 6 mL tube was added potassium tert-butoxide, 1.0 m solution in 2-methyl-2-propanol (2.431 mL, 2.431 mmol). The reaction was heated to 80° C. After 7 min a mixture of products was observed by LC/MS. The mixture was diluted with DCM (30 mL), and washed with water (3×25 mL) and brine (30 mL). It was dried over magnesium sulfate, concentrated and dried in vacuo. It was purified by flash chromatography (40 g SiliaSep pre-packed silica gel column, eluent: 0-40% EtOAc in hexane) to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 532.0 (M+1).
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:8])[CH:6]=[O:7])C.[NH2:9][CH:10]=[C:11]([CH3:14])C=O.O.[C:16]1(C)[CH:21]=CC=C[CH:17]=1>>[CH3:14][C:11]1[CH:10]=[N:9][C:8]2[CH2:17][CH2:16][CH2:21][C:6](=[O:7])[C:5]=2[CH:4]=1
Reactant: Cc1ccccc1
Reactant: CCOC=C(C)C=O
Reactant: CC(C=O)=CN
Solvent: O
Product: Cc1cnc2c(c1)C(=O)CCC2
Reaction time: 48 h
Yield: 4 %

Procedure:
A mixture of 3-aminocyclohex-2-enone (11.1 g. 0.1m) and 3-amino-2-methylacrolein (8.5 g. 0.1 m) in toluene (15 ml.) was heated at reflux below a Dean and Stark water separator for 48 hours. The solvent was removed and the residual oil distilled at 0.2 mm Hg to give the title compound as a colourless crystalline solid (0.5 g, 4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH3:30]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[CH3:30]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(OC)c1nc2c(cc1C)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 50 mg, 0.105 mmol), trimethylboroxine in (50% in THF, 39.6 mg, 0.158 mmol), Na2CO3 (2 M in water, 0.053 ml, 0.105 mmol), PdCl2(PPh3)2 (7.38 mg, 10.52 μmol) and DME (1 ml) were charged into a sealed vial under argon. The mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted in EtOAc and washed 2× with water and 1× with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 58:42). The product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.37 min; ESI-MS 411.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:29]=[C:30]=[S:31])[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.O1CCN(CCCN=C=S)CC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][NH:11][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[S:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: S=C=NCCCN1CCOCC1
Reactant: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Solvent: ClC(Cl)Cl
Product: S=C(NCCCN1CCOCC1)NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To a solution of N-(4-bromobenzyl)-N-(pyridin-2-yl)pro-pane-1,3-diamine (1.0 g, 3.123 mmol) in chloroform (40 ml) was added 3-morpholinopropyl isothiocyanate (593 mg, 3.123 mmol) and the reaction mixture was stirred for 20 h at reflux temperature. To the reaction mixture was added 10 drops of 3-morpholinopropyl isothiocyanate and the reaction mixture was stirred for an additional 4 h at reflux temperature. The volatiles were evaporated in vacuo and the residue (2.05 g) was dissolved in ethyl acetate (20 ml) and left over night at room temperature. The precipitate was filtered off and washed with ethyl acetate and dried affording 1.20 g (76%) of the title compound as a solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)(C)C>[CH:27]1([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCC2CCCCC2)CO3)N1
Temperature: 80 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.80 g, 2.13 mmole), and cyclohexylmethylamine (1.33 g, 11.7 mmole) were combined in 15 ml of dry DMSO and heated to 80° C. for 6 hours under a nitrogen atmosphere. The reaction was allowed to cool and was partitioned between 100 ml of ethyl acetate and 150 ml of deionized water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield a black oil. This oil was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 to remove impurities. A concentration of 2% methanol/CH2Cl2 eluted the desired product, which was as an oil (0.38 g, 56%) upon concentration in vacuum. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.15 g, 1.3 mmole) in hot isopropanol to give 0.39 g of the (S) enantiomer of the title compound as an off-white solid monofumarate, half hydrate, m.p. 187-188° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([C:42]#[N:43])=[C:40]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[N:39]=[C:38]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:37]=2[C:63]#[N:64])=[CH:32][CH:31]=1)=[O:25])[CH3:23])=[O:20])[CH2:10][NH:11]C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69]>ClCCl.C(OCC)C>[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].[NH2:11][CH2:10][C@@H:9]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:41]([C:42]#[N:43])=[C:40]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[N:39]=[C:38]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=4)[S:54][CH:55]=3)[C:37]=2[C:63]#[N:64])=[CH:34][CH:35]=1)=[O:25])[CH3:23])=[O:20])[NH2:8]
Reactant: C[C@H](NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H](N)CN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
290 mg (0.311 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)-L-alanyl-L-alaninate were dissolved in 5 ml dichloromethane, and 3.113 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, a further 3.113 ml of a 1N solution of hydrogen chloride in diethyl ether were added and the mixture was stirred at room temperature overnight. Another 10 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and stirring at room temperature was continued for a further 24 hours. The precipitated solid was then filtered off with suction, washed with diethyl ether and dried under reduced pressure. The crude product was dissolved in 2 ml of dichloromethane, and 0.126 ml (1.632 mmol) of trifluoroacetic acid was added. After 6 hours of stirring, the reaction mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). 81 mg (27% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)=O.O>C1(C)C=CC=CC=1.CO>[CH2:1]([NH:8][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Temperature: 105 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a solution of benzylamine (99 μl; 98 mg; 0.91 mmol) in anhydrous toluene (3 mL) placed in a sealed tube under nitrogen was added a solution of trimethylaluminum (365 μl; 2 M; 0.73 mmol) in toluene. The colorless solution was stirred at 25° C. for 1 h, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (50 mg; 0.18 mmol) was added and the resulting yellow suspension was heated to 105° C. overnight. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting blue suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide (26 mg, 39%) as a gray solid (HPLC: 95%, RT: 6.04 min). 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.39 (s, 1H), 8.82 (t, J=5.9 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 7.79 (d, J=5.5 Hz, 1H), 7.36-7.33 (m, 5H), 7.27-7.22 (m, 1H), 6.43 (dd, J=3.3, 1.8 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H); MS (m/z) 350 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:28]#[C:27][C:26]([OH:31])([CH3:25])[CH2:29][CH3:30])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#CC(C)(O)CC
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CCOCC
Solvent: CO
Product: CCC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 3-methyl-1-pentyn-3-ol were reacted in the presence of CuI and (PhP3)2PdCl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2-10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamide (77%) as a white solid; m.p. (CH2Cl2/Hexane) 127–131° C.