Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:18][C:8]1[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]2[NH:12][C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][CH:3]=[C:2]([N:1]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH:14]=3
Reactant: ClCCOCCCl
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 200 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide (250 mg, 0.822 mmol), 1-chloro-2-(2-chloroethoxy)ethane (0.387 mL, 3.29 mmol), sodium carbonate (697 mg, 6.58 mmol) were mixed in DMF (4 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated in microwave at 200° C. for 2 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 374.01 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)=[N:11][CH:12]=[C:13]([CH:15]=[CH:16][O:17]C)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]=[O:17])[CH:12]=[N:11][C:10]=1[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=Cc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(CC=O)cc2OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A 250 mL round-bottomed flask was charged with N-(3-(benzyloxy)-5-(2-methoxyvinyl)pyridin-2-yl)-4-methylthiazol-2-amine (1.93 g, 5.46 mmol) and THF (25 mL). 1M HCl (27.3 ml, 27.3 mmol) was added and the reaction was stirred at 50° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (30 to 50% EtOAc/hexanes) to afford the title compound (1.0 g, 54.0% yield) as a clear and colorless oil. 1H NMR (CDCl3) δ 9.75 (t, 1H), 8.55 (s, 1H), 7.82 (m, 1H), 7.40 (m, 5H), 6.96 (d, 1H), 6.40 (m, 1H), 5.09 (s, 2H), 3.66 (d, 2H), 2.32 (s, 3H). Mass spectrum (apci) m/z=340.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:24])[CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Reactant: C1COCCN1
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)N3CCOCC3)c2)c1)C(=O)OC(C)(C)C
Yield: 95.3 %

Procedure:
Using 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) and morpholine (42 mg), a procedure as in Reference Example 284 was performed to give the title compound as a colorless oil (yield 164 mg, 95%).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (80 mg, 19%).
Reaction SMILES: [O-]CC.[Na+].C(O)(=O)C.[CH3:9][CH:10]([CH3:15])[CH2:11][C:12](=[NH:14])[NH2:13].Cl.C(O[C:20](=[NH:27])[CH2:21][C:22](OCC)=[O:23])C.Cl>C(O)C.O>[NH2:27][C:20]1[N:13]=[C:12]([CH2:11][CH:10]([CH3:15])[CH3:9])[N:14]=[C:22]([OH:23])[CH:21]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CC(C)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Cc1nc(N)cc(O)n1
Yield: 43.5 %

Procedure:
Sodium ethoxide (210 mL of a 21% solution in ethanol, 563 mmol) was diluted with absolute ethanol (290 mL). To the sodium ethoxide solution were then sequentially added 3-methylbutanimidamide acetate (45 g, 281 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (59 g 85% purity, 256 mmol) and the mixture was heated to reflux overnight. The mixture was cooled down, solvent was stripped off and the residue was diluted with water (100 mL). pH was adjusted to 6-7 with 2 N HCl and the slurry was heated to reflux. Water (350 mL) was added although total dissolution of the solids was not achieved. The solids were collected by filtration and dried under vacuum to yield 18.6 g of the title compound. Upon cooling additional product precipitated, that was isolated by filtration and dried under vacuum to yield additional 8.18 g of product. The combined solids accounted for a total of 26.8 g (yield: 62%).
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1cccc(C=O)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCC#Cc1cccc(CNCc2ccc(C(F)(F)F)cc2)c1
Yield: 37 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 3-dodec-1-ynylbenzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound (37%). M+(LC/MS(ESI)): 430.5. HPLC (Condition A), Rt: 4.82 min (HPLC purity 94.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:33][C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=3)[C:26]([OH:35])=[O:25])[CH2:2][CH2:3]2)=[CH:8]1
Reactant: c1ccc(CCn2cc(C3CCNCC3)c3ccccc32)nc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCc4ccccn4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.4 g (11 mmol) of 3-piperidin-4-yl-1-(2-pyridin-2-yl-ethyl)-1H-indole and 2.7 g (11.5 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up and recrystallisation with dichloromethane/methanol, 1.4 g (29% of yield) of the expected acid were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26]>COCCO>[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH:26][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Cc1nc(Cl)cc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)nc(C)n1

Procedure:
To the compound 6-chloro-2-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.16 mmol) in 1 mL of 2-methoxyethanol is added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g, 0.16 mmol). The mixture is stirred at 110° C. until formation of the desired compound. The mixture is basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The compound can be purified by chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH3:22].O>CC(C)=O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH3:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a stirred mixture of 1-(4-bromophenyl)piperazine (4.82 g, 20 mmol) and K2CO3 (5.44 g, 40 mmol) in acetone (200 mL) was added iodoethane (2.58 mL, 32 mmol) dropwise over 1 min. After addition, the resulting mixture was stirred at rt for 24 h. The resulting precipitate was filtered off and rinsed with EtOAc (2×30 mL). The filtrate was concentrated to dryness to give a white solid which was treated with H2O (60 mL). Extraction with EtOAc (100 mL+60 mL) followed by concentration gave the crude title compound as a white solid. Trituration with MeOH (40 mL) gave first crop as a white solid (1.30 g). The mother liquor was concentrated to dryness and the trituration was repeated with MeOH, hexane and H2O to give additional 3.60 g as white solid. Total: 4.90 g (91%). 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=7.6 Hz, 2H), 6.87 (d, J=7.6 Hz, 2H), 3.13-3.03 (m, 4H), 2.49-2.40 (m, 4H, partially overlapping with DMSO signal), 2.34 (q, J=6.8 Hz, 2H), 1.01 (t, J=6.8 Hz, 3H); MS ESI 269.0 [M+H]+, calcd. for [C12H17BrN2+H]+ 269.1
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[C:16]=3[Cl:33])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:34]>CO.O1CCOCC1>[ClH:33].[ClH:34].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:16]=3[Cl:33])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 3-[(4-{[(1-adamantylmethyl)amino]carbonyl}-3-chloropyridin-2-yl)amino]propylcarbamate (0.41 g) Example 36(i)) in methanol (15 ml) was treated with a solution of HCl in 1,4-dioxane (4 ml) and the mixture was stirred at room temperature for 18 hrs. The solution was evaporated. Methanol was added and the solution was evaporated to give the title compound as a pale yellow solid.
Reaction SMILES: ClC1C=CC(COC2C=NNC(=O)C=2)=NC=1.[F:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23][C:24]2[CH:29]=[N:28][N:27](C3CCCCO3)[C:26](=[O:36])[CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23][C:24]2[CH:29]=[N:28][NH:27][C:26](=[O:36])[CH:25]=2)=[CH:37][CH:38]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cnn1C1CCCCO1
Agent: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Product: O=c1cc(OCc2ccc(F)cc2)cn[nH]1

Procedure:
5-(4-Fluoro-benzyloxy)-2H-pyridazin-3-one is prepared following preparation 18b from 10.5 g (34.5 mmol) 5-(4-fluoro-benzyloxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 26a).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(C[C:32]([NH:34]CN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.CN>CS(C)=O.C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:23]=[C:22]([NH:34][CH3:32])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 135 °C
Yield: 73 %

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and diisopropylethylamine (0.5 mL), methylamine (2M tetrahydrofuran solution) (2 mL, 4 mmol) was added thereto, followed by heating in a sealed tube for 14 hours (oil bath temperature: 135° C.). The reaction mixture was allowed to room temperature, poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (144 mg, 0.41 mmol, 73%) was obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:10]=1[OH:16].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([S:15][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: Oc1ccc(S)cc1Cl
Reactant: O=Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(CSc2ccc(O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
Triethylamine (5.0 mL, 35.9 mmol) was added dropwise to a solution of 2-chloro-4-mercaptophenol (3.60 g, 22.4 mmol) and 4-bromomethyl benzaldehyde (3.93 g, 19.7 mmol) in dioxane (150 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 20 hours. Water (100 mL) was added to the reaction mixture and it was then partitioned with ethyl acetate and brine (200 mL each). The aqueous layer was re-extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo affording a yellow solid. This was purified by trituration with acetonitrile (5 mL/g) for 30 minutes. After filtration this afforded a light yellow solid as the pure product, 84% yield, 5.27 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.C(N)CN.BrCC1C=CSN=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[O:25]
Reactant: NCCNCc1ccsn1
Reactant: CN=C=O
Agent: BrCc1ccsn1
Solvent: NCCN
Product: CNC(=O)NCCNCc1ccsn1

Procedure:
N-(3-Isothiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 3-bromomethylisothiazole by the procedure of Example 40(a), is reacted with methyl isocyanate by the procedure of Example 24 to give, after concenrating and separating by column chromatography, the title compound.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][N:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC=C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CC=Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,3-dip-tolyl-5,6-dihydropyrido[2,3-b]pyrazine (Example 8.2 step 1) (3.88 g, 12.38 mmol) in DCE (70 ml) was added ethyl 7-oxoheptanoate (6.40 g, 37.1 mmol) followed by sodium triacetoxyborohydride (10.4 g, 49.1 mmol). The reaction mixture was stirred for 2 days at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water (70 ml) and extracted with EtOAc (3×70 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification using reverse phase chromatography eluting with MeCN/water (0.1% TFA) to afford the title compound;
Reaction SMILES: [CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43](Br)=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][CH2:49][CH2:50][OH:51].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:51][CH2:50][CH2:49][O:48][CH3:47])=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([C@H](Cc1ccccc1)N(Cc1ccc(Br)nc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Reactant: COCCO
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
In an inert atmosphere, N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(6-bromo-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (80 mg, 0.116 mmol), was dissolved in dry toluene (3 mL) followed by the addition of 2-methoxy-ethanol (11.4 mg, 0.15 mmol), tris-(dibenzylideneaceton)-dipalladium (2.1 mg, 0.002 mmol), xanthphos (4 mg, 0.007 mmol) and sodium tert.-butoxide (16.7 mg, 0.174 mmol). The mixture was heated to 50° C. and stirring continued for 90 min. The reaction mixture was cooled to rt, brine (5 mL) was added and the product was extracted with EtOAc (3×4 ml). The combined organic layers were concentrated under reduced pressure and the residue was purified by prep. HPLC to give 38 mg (47%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-[6-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide. (LC-MS: tR=1.06 min; [M+H]+=687.27).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]12.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]2[C:2]1=[O:1]
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of tert-butyl (4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (44 mg, 0.13 mmol) in DCM (1 mL) was added TFA (1.0 mL, 13 mmol). The reaction was stirred at rt for 1 hr. The reaction mixture was concentrated and dried under high vacuum to afford (4S,7S,10aS)-4-amino-7-vinylhexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one trifluoroacetate (46 mg, 0.134 mmol, 100% yield) as an oil. Anal. Calcd. for C11H18N2OS m/z 226.3. found: 227.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[C:6]([F:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[OH-:16].[Na+]>>[F:13][C:7]1[C:6]([F:14])=[C:5]([OH:16])[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: [OH-]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])c(O)c(F)c1F

Procedure:
The solid 5-nitro-2,3,4-trifluorobenzoic acid (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22% yield; MS (APCl−) 218 (M−1, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>[OH-].[Na+]>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]3[CH2:14][C:15]([OH:17])=[O:16])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
3-Methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester (6.0 g) was dissolved in TBF (60 ml) and 1N sodium hydroxide solution (60 ml) and stirred at room temperature for 6 hours. The solution was then cooled to 5° C. and adjusted to pH 9-10 by the addition of 10% hydrochloric acid. Nα(9-Fluorenylmethoxycarbonyl chloride (6.05 g) was then added portionwise, maintaining the pH at 9-10 by the addition of 1N NaOH solution. The reaction mixture was stirred at 5° C. for 16 hours. The solution was then adjusted to pH 1 by the addition of 10% hydrochloric acid. The solution was extracted with ethyl acetate (×2), dried (MgSO4) and evaporated. The title compound was obtained as a white foam (9.96 g), mass spectrum (API+) 411 [(M-C4H8)H+], C26H30N2O6 requires 466.