Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[S-:14][CH2:15][CH3:16].[Na+]>>[CH2:15]([S:14][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: CC[S-]
Reactant: O=c1onc2n1C(CBr)CCCC2
Agent: [Na+]
Product: CCSCC1CCCCc2noc(=O)n21

Procedure:
The product of Example 37a or the product of Example 15 is reacted with sodium thioethoxide by the methods of Example 37 to generate the title material.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>C(#N)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncc(-c2ccccc2)s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1ncc(-c2ccccc2)s1)n1ccnc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To 5-phenylthiazol-2-amine (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added 1,1′-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65° C. for 2 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)-1H-imidazole-1-carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65° C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3=375.33).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O.ClCCl>[CH2:28]([O:27][C:21]1[CH:22]=[C:23]([N:35]2[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])=[O:30])[CH3:29]
Reactant: CN1CCCNCC1
Reactant: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 65.6 %

Procedure:
5-Fluoro-2-[4-fluoro-2-ethoxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (135 mg, 0.31 mmol) and 1-methylhexahydro-1,4-diazepine (177 mg, 1.55 mmol, 5 eq) were dissolved in 250 μL DMSO, in a 4 mL screw cap vial. The pale yellow solution was incubated at 100° C. for 36–40 hours. The solution was cooled, diluted with 12 mL of dichloromethane, washed four times with water, once with brine, then dried over sodium sulfate and concentrated in vacuo. The crude residue was purified first by chromatography on a silica gel cartridge (2 g/12 cc, Varian Sample Preparation Products, Harbor City, Calif.) using zero to ten percent methanol in dichloromethane, then by radial chromatography with zero to ten percent methanol in dichloromethane. Pure fractions were pooled, concentrated in vacuo and dried under high vacuum to yield 107 mg (65%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)CC1
Yield: 99.1 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-(trifluoromethyl)benzoyl chloride (104 μl, 0.687 mmol), 88.6 mg (99%) of the title compound were recovered.
Reaction SMILES: [C:1]([O:11]C)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:13]>CO>[C:1]([NH2:13])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N
Reactant: COC(=O)C=Cc1ccccc1
Solvent: CO
Product: NC(=O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A solution of methyl cinnamate (28 mmol) and 7M ammonia in MeOH (30 ml) was sealed in a 100 ml thick-wall round bottom flashed, and heated at 90° C. with stirring for 72 h, resulting in a brown solution. After the solvent was removed by a rotary evaporator, the crude products were purified by flash silica gel chromatography (eluting with 2-10% MeOH in DCM) to afford cinnamamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:12]1[C:13]([S:18][CH3:19])=[N:14][CH:15]=[N:16][CH:17]=1.[F:21][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:12]1[C:13]([S:18][CH2:19][F:21])=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: F[B-](F)(F)F
Reactant: CSc1ncncc1C1c2ccccc2CCC1(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC1(C)CCc2ccccc2C1c1cncnc1SCF
Yield: 33.1 %

Procedure:
To a solution of 2.0 g (7.0 mmol) of 5-(2,2-dimethyltetralin-1-yl)-4-methylthiopyrimidine in 100 mL of dry acetonitrile was added with stirring 3.0 g (9.1 mmol) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). The mixture was allowed to react for 16 hours and then most of the acetonitrile was removed by evaporation under reduced pressure. The residue was partitioned between ether and water and the organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual oil was purified by column chromatography on silica gel to obtain 700 mg of the title compound as a tan solid melting at 126°-128° C.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:30][CH:31]=1)#[N:2]
Reactant: Brc1cccnc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2cccnc2)cc1F

Procedure:
In analogy to example 57.1 (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methoxy-acetamide was reacted with 3-bromopyridine to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-pyridin-3-yl-phenyl)-2-methoxy-acetamide. Light brown amorphous solid. MS 376.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[CH:20]=[CH:21][CH:22]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40]C3CCCCO3)[CH2:34][CH2:33]2)[N:3]=1.Cl>CCOC(C)=O>[OH:40][CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][N:32]([C:4]2[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]4[C:14]([C:17]5[CH:18]=[C:19]([NH:23][C:24]([NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[O:25])[CH:20]=[CH:21][CH:22]=5)=[CH:15][N:16]=[C:10]4[CH:9]=3)[CH:5]=2)[CH2:33][CH2:34]1
Reactant: Cc1nc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc(N2CCN(CCOC3CCCCO3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To 1-{3-[7-(2-Methyl-6-{4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperazin-1-yl}-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (150 mg) treated with saturated HCl in EtOAc, reaction stirred RT for 1 hour, precipitated solid filtered and washed with EtOAc. The crude product was purified by preparative HPLC twice to give product (30 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: CCCCN
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Temperature: 90 °C
Reaction time: 70 h

Procedure:
A stirred mixture of the product from step (i) (8 g) and butylamine (7.40 ml) in dioxane (100 ml) was heated at 90° C. for 72 h. More butylamine (7.40 ml) was added and the reaction mixture stirred for a further 70 hrs. The solvent was evaporated and the crude product was purified by chromatography (5% MeOHiDCM) to afford the subtitle compound as a tan solid, 4.5 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:63])[C:59]([F:62])([F:61])[F:60]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:63][C@@H:58]([C:52]2[CH:53]=[CH:54][C:55]([F:57])=[CH:56][C:51]=2[F:50])[C:59]([F:60])([F:62])[F:61])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: N[C@@H](c1ccc(F)cc1F)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(N[C@@H](c1ccc(F)cc1F)C(F)(F)F)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine hydrochloride (EXAMPLE 29, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H14BrF5N4O3S, 600.0; m/z found, 599/601 [M−H]−. HPLC (reverse phase): RT=10.06 min. 1H NMR (400 MHz, CDCl3): 11.02 (s, 1H), 8.84-8.83 (m, 2H), 8.56 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.43-7.37 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.13 (dd, J=8.5, 1.8 Hz, 1H), 7.03-6.93 (m, 2H), 6.82-6.80 (m, 1H), 6.06-5.99 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH:22]=[CH2:23].C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:23]([O:19][C:18](=[O:20])[C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:22]=[CH2:21]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-(t-Butoxycarbonyl)-D-homophenylalanine (2.0 g; 7.16 mmol), allyl alcohol (500 ml; 7.35 mmol) and 4-dimethylaminopyridine (88 mg; 0.72 mmol) were dissolved in dry methylene chloride and stirred at room temperature. EDC (1.4 g; 7.30 mmol) was added to the solution in small batches over 15 minutes and the reaction mixture stirred at room temperature for 6 h. The reaction was quenched by pouring the reaction mixture into water (10 ml) and extracted with methylene chloride (2×25 ml). The combined methylene chloride extracts were washed successively with 5% aqueous citric acid solution (50 ml) and a 10% aqueous sodium carbonate solution. The methylene chloride layer was dried over anhydrous magnesium surf ate powder, filtered and evaporated to leave a thick oily residue which was purified by column chromatography on silica gel using an eluant comprising ethyl acetate and hexanes in the ratio 2:1. The yield of the desired allyl ester product was 1.96 g (85.7%). FAB-MS:- calculated for C18 H25NO4 319.2; found 320. (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:18](OCC)=[O:19])[N:9]2[CH2:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:5][CH:4]=1.CC(C)(C)C([O:29][CH2:30][C:31]1[S:32][C:33]2[C:38]([N:39]=1)=[CH:37][C:36]([NH2:40])=[CH:35][N:34]=2)=O.C[Al](C)C>>[OH:29][CH2:30][C:31]1[S:32][C:33]2[C:38]([N:39]=1)=[CH:37][C:36]([NH:40][C:18]([C:8]1[N:9]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[C:10]3[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([Si:2]([CH3:24])([CH3:23])[CH3:1])[CH:11]=3)=[O:19])=[CH:35][N:34]=2
Reactant: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2n1Cc1nccs1
Reactant: CC(C)(C)C(=O)OCc1nc2cc(N)cnc2s1
Agent: C[Al](C)C
Product: C[Si](C)(C)c1ccc2cc(C(=O)Nc3cnc4sc(CO)nc4c3)n(Cc3nccs3)c2c1
Yield: 149.9 %

Procedure:
This compound was prepared according to a process similar to that described in step 16.2, by reacting 200 mg (0.523 mmol) of ethyl 6-trimethylsilyl-1-[(thiazol-2-yl)]methyl-1H-indole-2-carboxylate, prepared in the preceding step, with 178 mg (0.670 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate, obtained in step 4.2, in the presence of 0.39 mL (0.784 mmol) of a solution of trimethylaluminium (2M/toluene). The product was isolated by purification by chromatography on a column of silica, eluting with a mixture of dichloromethane and ethanol. 120 mg of the expected product are obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH2:26])=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:36][C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[N:23][C:22]=3[Cl:27])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Reactant: COc1ccc(C=O)cn1
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1

Procedure:
5-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine (592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme 183) was combined with 6-methoxy-pyridine-3-carbaldehyde (618, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound 619, which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[CH:12](=O)[CH:13]([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1/[N:5]=[CH:12]/[CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1/N=C/C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzene (150 mL) was added to 2,6-diethylaniline (18.59 g, 124.6 mmol) and 3 angstrom molecular sieves (ca. 50 mL). Then isobutyraldehyde (9.43 g, 131 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.011 mmol) were added. The flask was sealed and heated to 50° C. After stirring overnight the very pale yellow solution was filtered and the volatiles were removed under reduced pressure to afford the product as a clear, pale yellow oil. Yield: 22.5 g, 84.6%. 1H NMR (C6D6): δ 7.21 (1H, d), 7.02 (2H, m), 2.47 (4H, q), 2.39 (1H, m), 1.11 (6H, t), 1.01 (6H, d).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([CH:15]([CH:19](CC=C)[C:20]([NH2:22])=[O:21])[C:16]([NH2:18])=[O:17])C=C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([CH:19]([C:20]([NH2:22])=[O:21])[CH2:15][C:16]([NH2:18])=[O:17])=[N:2]1
Reactant: C1=Cc2ccccc2NN=C1
Reactant: C=CCC(C(N)=O)C(CC=C)C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(C(N)=O)C1=NNc2ccccc2C=C1

Procedure:
Following the procedures described for the synthesis of 11, diallylsuccinamide intermediate 16 was prepared from 14 in reasonable yield. 14 (2.5 g, 5.9 mmol), p-chloro-BZD (2.34 g, 6.2 mmol) and DIPEA (1 ml, 5.8 mmol) in 30 ml DMF was heated to 40-50 degree overnight.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH3:1][N:2]([CH2:3][C:4]([OH:6])=[O:5])[C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: CNCC(=O)O
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)C(=O)Nc1ccccc1
Temperature: 24 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 70 g. of N-methylaminoacetic acid in 500 ml. of water containing 70 g. of sodium hydroxide were added portion-wise over twenty minutes 100 g. of phenyl isocyanate. Following complete addition, the aqueous reaction mixture was stirred at 24° C. for two hours. The mixture was then filtered and the filtrate was acidified to pH 2 by the addition of conc. hydrochloric acid. The precipitate which formed was collected by filtration to provide N-methyl-N-hydroxycarbonylmethyl-N'-phenylurea.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2>ClCCl>[C:1]([NH:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:25])([CH3:26])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)Oc2ccsc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccccc2)C1O

Procedure:
The title compound was prepared as described in Example 34 starting with benzoyl chloride (0.95 ml), triethylamine (3.3 ml, 23 mmol) and 7-amino-5,6-dihydro-6-hydroxY-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.55 g, 7.78 mmol) in dichloromethane (35 ml) to give the product 1.07 g (45%) as a colorless solid; mp 219°-220° C.; IR(KBr):3398, 1657, 1526 and 1490 cm-1 ; MS:m/z 304 (MH+); 1H NMR (DMSO-d6):δ 1.21 (5,3H), 1.39 (5,3H), 3.81 (m,1H, simplifies to d, J=8.8 Hz, with D2O), 5.00 (m,1H simplifies to d, 5=8.8 Hz, with D2O), 5.61(d,J=6.0 Hz, 1H, exchanges with D2O), 6.58(d,J=5.3 Hz,1H), 7.29(d,J=5.3 Hz,1H), 7.47(m,3H), 7.92 (dd,J=1.3 Hz, J=8.2 Hz,2H) and 8.79 (d,J=8.3 Hz, 1H, exchanges with D2O).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([C:14]2[O:15][C:7]3[CH:6]=[CH:12][CH:13]=[CH:8][C:9]=3[CH:10]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc2oc(C3CCCCC3)cc2c1
Yield: 147.6 %

Procedure:
A mixture of 13 g (0.0289 mole) of the above product, 8.77 g triethylamine and 4.66 g (0.0318 mole) cyclohexylcarbonyl chloride and 120 ml toluene was heated at reflux under nitrogen for six hours, cooled, filtered to remove insoluble matter and the filtrate concentrated in vacuo. The residual solid was flash chromatographed, eluting with hexane to obtain 4.7 g (81%) of white crystals, m.p. 32°-34° C. Mass spectrum (m/e): 200 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:31]([CH3:32])[CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CNC
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CN(C)C(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and dimethylamine gave 101. MS: (ESI+) 441.1.
Reaction SMILES: C([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][C:16]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:21])=[O:11])(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][C:16]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)=[O:21])=[O:11]
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CN)cc1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of N-(2-(N-(N-carbo-tert-butoxyglycyl)aminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.050 g, 0.105 mmol) in CH2Cl2 (3 mL) at room temp. was added trifluoroacetic acid (0.50 mL, 6.49 mmol, 62 equiv). The resulting mixture was stirred for 3 h, washed with a saturated NaHCO3 solution, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (for CH2Cl2 to 20% MeOH/CH2Cl2) to give N-(2-(N-glycylaminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.019 g, 48%): mp 93-6° C.; 1H NMR (CDCl3) δ1.14 (s, 9H), 2.08 (s, 3H), 3.89 (s, 2H), 4.34 (br s, 7H), 6.67 (s, 1H), 6.87 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.3 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[C:13]([CH:15]=[CH:16][NH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)[CH:2]=[CH2:3].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)(C)C>[CH2:1]([C:4]1[CH:14]=[C:13]([CH:15]=[CH:16][NH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:25][CH:22]([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=CNC(=O)OC)ccc1OCC1CO1
Reactant: CC(C)N
Solvent: CC(C)O
Product: C=CCc1cc(C=CNC(=O)OC)ccc1OCC(O)CNC(C)C

Procedure:
4.9 g (0.017 mol) of 1-[2-allyl-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are heated for 3 hours with a solution of 1.57 ml (0.018 mol) of isopropylamine in 100 ml of isopropanol to 80° C. under reflux. The mixture is then evaporated under reduced pressure and the resulting crude base is crystallised from acetone-ether. 1-[2-Allyl-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylamino-propane, of melting point 128°-129° C. is obtained.