Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][CH:19]([OH:22])[C:20]#[CH:21]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[OH:22][CH:19]([CH3:18])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Reactant: C#CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
6.78 g (20 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 7 hours with 1.75 g (25 mmol) of 3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 50 ml of diethylamine and 30 ml of ethylene chloride. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate and hexane there was obtained 4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 161°-162°.
Reaction SMILES: O[C:2]1[N:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CC1C(=[S:19])CN=NN=1.CC1C(=O)CN=NN=1>>[SH:19][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC1=NN=NCC1=S
Reactant: Oc1nnc2ccccc2n1
Agent: CC1=NN=NCC1=O
Product: Sc1nnc2ccccc2n1

Procedure:
3-Mercapto-1,2,4-benzotriazine was prepared from 3-hydroxy-1,2,4-benzotriazine and 6-methyl-1,2,3-triazine-5(4H)-thione from 6-methyl-1,2,3-triazine-5(4H)-one following essentially the above procedure.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.O>[CH2:14]([O:6][C:5](=[O:7])[C@@H:2]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][OH:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
A solution of L-serine (2.1 g, 20 mmol) in acetonitrile/water (52 mL, 25:1) was added to solid potassium carbonate (13.8 g, 100 mmol) and the mixture was treated with benzyl bromide (8.92 mL, 75 mmol). After stirring for 20 h at 55° C. the mixture was cooled to room temperature, filtered, diluted with ethyl acetate and the organics were washed with water, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.9 g, 52%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.52 (dd, J=7.3, 4.5 Hz, 1H), 3.61 (d, J=7.6 Hz, 1H), 3.67 (d, J=13.6 Hz, 2H), 3.75-3.85 (m, 2H), 3.92 (d, J=13.6 Hz, 2H), 5.23, 5.32 (ABq, JAB=12.0 Hz, 2H), 7.22-7.37 (m, 10H), 7.38-7.48 (m, 5H). LCMS (m/z) 376.2 [M+H], Tr=3.25 min.
Reaction SMILES: CC1C=CC(CP(=O)OCC2C=CC=CC=2)=CC=1.[H-].[Na+].C([O:28][C:29]([CH:31]([CH2:45][CH2:46][C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:32][P:33]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:35])[OH:34])=[O:30])C1C=CC=CC=1.Cl>C1COCC1.CCOC(C)=O>[C:39]1([CH2:38][CH2:37][CH2:36][P:33]([CH2:32][CH:31]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:29]([OH:30])=[O:28])([OH:35])=[O:34])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cc1ccc(C[PH](=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 163 %

Procedure:
To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl) (2.16 g, 8.3 mmol) in THF (15 mL) was added sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylenepentanedioate (3) (3.24 g) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with EtOAc (50 mL) and poured into 1 N HCl (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This material was purified by silica gel chromatography (hexanes: EtOAc, 4:1 to 1:1) to give 3.41 g of 2,4-di(benzyloxycarbonyl)-butyl(4-methylbenzyl)-o-benzylphosphinic acid (4, R=4-methylbenzyl) as colorless oil (70% yield). Rf 0.61 (EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Br)cc1
Yield: 88 %

Procedure:
A solution of 4-bromobenzylsulfonyl acetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 88% yield.
Reaction SMILES: CCO[C:4]([CH2:6][CH2:7][CH2:8][P:9]([O:14]CC)([O:11]CC)=[O:10])=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].O>Cl>[N:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:24][C:4]=1[CH2:6][CH2:7][CH2:8][P:9]([OH:11])(=[O:10])[OH:14]
Reactant: CCOC(=O)CCCP(=O)(OCC)OCC
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: O
Product: O=P(O)(O)CCCc1nc2ccccc2[nH]1
Yield: 50.8 %

Procedure:
If 110 g (0.43 mol) of triethyl 4-phosphonobutyrate and 48.6 g (0.45 mol) of o-phenylenediamine are reacted with one another in 200 g of concentrated HCl and 200 g of H2O according to Example 1, 52.5 g (51.5% of theory) of 3-[benzimidazol-2-yl]-propanephosphonic acid are obtained as light grey crystals with a melting point of about 280° C. (decomposition). ##STR19##
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][C@@H:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]3[C@H:10]2[O:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>O.CO.C(Cl)Cl>[N:28]([C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:9]([O:8][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:10]1[OH:11])=[N+:29]=[N-:30]
Reactant: c1ccc(C(O[C@@H]2CCC[C@H]3O[C@H]32)(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=N[C@H]1CCC[C@@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1O
Temperature: 80 °C
Yield: 62 %

Procedure:
The diastereomeric mixture of (1R,2R,6R)-2-(triphenylmethoxy)-7-oxabicyclo[4.1.0]heptane 1 (755 mg, 2.12 mmol) and the S,S-epoxide was dissolved with NaN3 (861 mg, 13.3 mmol) in H2O (1.7 mL) and MeOH (15 mL). The mixture was heated to 80° C., refluxed over night and then diluted with water and CH2Cl2. The organic layer was separated and the aqueous layer was rewashed (CH2Cl2). The entire organic layer was dried (MgSO4), filtered and concentrated. Purification was made by recrystallization in MeOH at −18° C. The reaction yielded 62% of 2. 1H-NMR (CDCl3) 7.50 (m, 6 H), 7.20-7.40 (m, 9 H), 3.69 (t, J=9.50 Hz, 1 H), 3.05 (ddd, J=4.80, 9.44, 12.05 Hz, 1 H), 2.91 (ddd, J=4.17, 8.81, 11.28 Hz, 1 H), 2.70 (s, 1 H), 1.80 (m, 1 H), 1.50 (m, 2 H), 1.20-1.40 (m, 2 H), 0.80 (m, 1 H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOCC>[CH2:16]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: Oc1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C#CCOc1cccc2ccccc12
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Into a reaction flask fitted with a stirrer, a thermometer, a nitrogen gas inlet tube and a reflux condenser, was placed 21.259 parts of 1-naphthol, 53.086 parts of deionized water, 6.675 parts of NaOH and 0.120 part of tetrabutylammoniumbromide and to this mixture, 18.859 parts of propargyl bromide was added dropwise and reacted at 80° C. for 6 hours. After completion of the reaction, the content was treated with a mixture of ether and deionized water and the ether layer was separated, added with magnesium sulfate and kept stand overnight. After filtering off magnesium sulfate, the ether solvent was removed by an evaporator and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1propargyloxynaphthalene. Yield 63.6%
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.36 mmol) in dioxane (5 mL) was added 2,4-difluorophenylboronic acid (113 mg, 0.72 mmol), K3PO4 (152 mg, 0.72 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (115 mg, 84%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[CH:30]1[C:35](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])=[CH:34][CH:33]=[C:32]([OH:41])[CH:31]=1>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:38]([O-:40])(=[O:39])/[CH:37]=[CH:36]/[C:35]1[CH:34]=[CH:33][C:32]([OH:41])=[CH:31][CH:30]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])/C=C/c1ccc(O)cc1
Temperature: 30 °C

Procedure:
Sunitinib (1.0 g) was suspended in methanol (152 mL), followed by addition of coumaric acid (0.41 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib coumarate.(1.1 g; yield:78%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2F)[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]2[C:16]3[C:15]([CH:13]([CH3:14])[N:12]([S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:10])=[O:11])[C:23]=2[CH:24]=1)=[CH:20][C:19]([F:21])=[CH:18][CH:17]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccc(F)cc3C2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A stirred suspension of 4-methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzenesulfonamide (0.74 g, 1.74 mmol) and potassium carbonate (0.48 g, 3.50 mmol) in N,N-dimethylformamide (5 mL) was heated for twelve hours at 100° C. The reaction mixture was cooled and poured into distilled water. After stirring overnight at room temperature, a precipitate was filtered and dried under high vacuum. The precipitate was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of 15% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after evaporation of the solvent, a colorless solid. Crystallization from diethyl ether-hexane yielded the title compound (0.67 g, 1.65 mmol, 95%) as a homogeneous, colorless, crystalline solid, m.p. 141-143° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][N:11]([C:24]([C:23]4[CH:27]=[C:19]([S:16]([CH3:15])(=[O:17])=[O:18])[CH:20]=[CH:21][C:22]=4[O:28][C@@H:29]([CH3:34])[C:30]([F:32])([F:33])[F:31])=[O:25])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Clc1ccc2sc3c(c2c1)CCNC3
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(sc3ccc(Cl)cc23)C1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 1 using 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine [29078-50-0] and 5-methylsulfonyl-2-[((S)-2,2,2-trifluoro-1-methylethyl)oxy]benzoic acid [845616-82-2]. MS (m/e): 518.1 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH2:9][C@@H:10]1[O:15][C:14](=[O:16])[N:13]([CH3:17])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH2:11]1.C(Cl)(Cl)Cl.C(=O)(O)[O-].[NH4+:36]>>[CH3:2][O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH2:9][C@@H:10]1[O:15][C:14](=[O:16])[N:13]([CH3:17])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[N:25][NH2:36])=[CH:20][CH:19]=2)[CH2:11]1
Reactant: [NH4+]
Reactant: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C#N)cc2)N(C)C(=O)O1
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C=NN)cc2)N(C)C(=O)O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
Dry HCl gas was bubled through a solution of 3-[[4(S)-(4-cyanophenyl)tetrahydro-3-methyl-2-oxo-2H-1,3-oxazin-6(R)-yl]acetyl]aminopropionic acid methyl ester (125 mg 0.35 mmol) in dry CHCl3 containing anhydrous methanol (23 mg, 0.70 mmol), cooled with salt ice-water bath, at 0° C. for 5 hrs. The resulting solution was then kept at 0° C. for 6 hrs and at 15° C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol (3 ml) followed by addition of ammonium bicarbonate (84 mg, 0.88 mmol). After stirring at rt for 4 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol as the eluent to give a white amorphous solid (85 mg, 64% yield).1H NMR (300 MHz, CD3OD) δ1.90 (m, 1H), 1.22(m, 2H), 2.50(t, 2H), 2.60(dd, 1H), 2.66(s, 3H), 3.40(m, 2H), 3.60(s, 3H), 4.80(m, 2H), 7.54(d, 2H), 7.84(d, 2H); MS (ESI) Calc. for (M+1)+: 377. Found: 377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:26][CH3:27])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (0.5 g, 1.76 mmol) in dry CAN (15 mL), cesium carbonate (1.2 g, 3.68 mmol) and ethyl iodide (2.7 g, 17.3 mmol) were added and the resulting reaction mixture was heated at 80° C. for 18 h. On completion, the mixture was cooled to room temperature and filtered with the residue washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford desired methyl 5-chloro-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.180 g, 34%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:40])[CH2:10][C:11]1([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42].O>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:40])[CH2:10][C:11]1([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:44]([NH:43][CH2:41][CH3:42])=[O:45])[CH:34]=3)=[CH:31][CH:32]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:12]1
Reactant: Nc1cccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(C(=O)c4ccccc4)CCS3(=O)=O)s2)c1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)Nc1cccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(C(=O)c4ccccc4)CCS3(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(3-aminophenyl)-2-thienyl)-4-benzoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (150 mg) in dichloromethane (3 ml) was added ethyl isocyanate (22 mg) at 0° C. and the reaction mixture was stirred at ambient temperature for 5 hours. The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel 60 (3% methanol-chloroform) to give N-(2-tetrahydropyranyloxy)-2-[4-benzoyl-7-(5-(3-(ethylaminocarbonylamino)phenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (75 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].[K].[OH-].[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CO.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Reaction time: 3 h
Yield: 41 %

Procedure:
1.65 g (10 mmoles) of 4,5-dichloro-3(2H)-pyridazinone are converted into potassium salt with an equimolar amount of potassium hydroxide dissolved in methanol, and the methanol is removed in vacuo. To the suspension of the salt in 30 ml of toluene a solution of 1.56 g (10 mmoles) of 4-methoxybenzyl chloride in 30 ml of toluene is dropped under stirring, then 0.6 g (1.8 mmole) of tetrabutyl ammonium bromide is added. The reaction mixture is boiled for 3 hours under reflux cooling and evaporated to dryness in vacuo. The residue is dissolved in water, then the solution is extracted with ethyl acetate, dried and evaporated. The crude product thus obtained is optionally subjected to column chromatography on a silica gel column using ethyl acetate as solvent. Thus 1.17 g (41% ) of the desired compound are obtained. M.p.: 117°-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([CH2:14][CH2:13][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-cyanophenol (5.95 g, 0.05 mol) in DMF (35 ml) at 0° C. is added 60% NaOH (2.2 g, 0.055 mol). The reaction mixture is stirred at 0° C. for 15 minutes, then at room temperature for 15 minutes and then N-(2-chloroethyl)morpholine (prepared from 11.16 g, 0.06 mol of the hydrochloride salt) is added, and the reaction mixture is stirred at room temperature for about two days. There is still a small amount of starting material present so the reaction mixture is heated on a steam bath for 4 hours. The reaction mixture is cooled to room temperature and then the solvent is removed. Ice water is added to the residue, and the solid which precipitats is collected by filtration and dried to afford 11.3 g (97%) of 4-[2-(4-morpholinyl)ethoxy]benzonitrile.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].C[O:12][C:13]1[C:14]([I:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1>>[CH2:5]([NH:7][C:8](=[O:9])[O-:10])[CH3:6].[OH:12][C:13]1[C:14]([I:26])=[CH:15][C:16]2[CH:17]([CH3:25])[CH:18]3[CH2:22][NH:21][CH2:20][CH:19]3[C:23]=2[CH:24]=1
Reactant: COc1cc2c(cc1I)C(C)C1CNCC21
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Product: CC1c2cc(I)c(O)cc2C2CNCC12
Reaction time: 8 h

Procedure:
BBr3 (0.7 mL, 0.7 mmol, 1 M in CH2Cl2) was added to a solution of N-ethylcarbamate-5-methoxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (120 mg, 0.3 mmol) at 0° C. The reaction mixture was stirred overnight from 0° C. to room temperature and quenched with H2O. The solution was filtered through an Extrelut column, the column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C15H18INO3+H: 388, observed: 388.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:35])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].C1COCC1>CO>[CH2:21]([N:17]1[C:18]2[C:13](=[C:12]([OH:35])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[O:10])=[N:20][CH:19]=2)[CH:14]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:16]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 4-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-butyric acid ethyl ester (38 mg, 0.078 mmol), 2M aq. NaOH (4 mL), THF (4 mL) and MeOH (4 mL) was stirred at r.t. for 16 h. Solvent was evaporated in vacuo to one-third of its original volume, and the mixture was placed in an ice bath. 1 M HCl was added until pH about 2, and the resulting precipitate was collected by filtration and dried to give 27 mg of the title compound as a pale yellow solid. MS: (+) m/z 458.36 (M+1).