Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:28][C:27]2[N:26]=[CH:25][CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[C:21](=O)[CH2:20]1>CO>[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:28][C:27]2[N:26]=[CH:25][CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[C:21](=[N:5][NH:4][C:1]([NH2:3])=[NH:2])[CH2:20]1
Reactant: N=C(N)NN
Reactant: COc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: COc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
To a solution of aminoguanidine hydrochloride (0.048 g) in methanol (20 ml) was added methanesulfonic acid (0.042 g), and the mixture was refluxed for 1 hour. To the mixture were added 7-(2-chlorophenyl)-4-methoxy-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) and methanesulfonic acid (0.042 g), and the mixture was stirred at 50° C. for 9 hours and at 60° C. for 16 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water-ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methoxy-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 79) (0.19 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:17][CH2:18][O:8][C:6]=2[CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cc(Br)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCCN2C1CCOCC1
Temperature: 180 °C
Yield: 56 %

Procedure:
A mixture of intermediate D9 (0.433 g, 1.591 mmol), 1,2-dibromoethane (0.411 ml, 4.773 mmol and potassium carbonate (1.099 g, 7.955 mmol) in DMF (10 ml) was heated at 180° C. for 15 min. under microwave irradiation. After cooling to r.t. the r.m. was filtered through diatomaceous earth. The filtrate was evaporated in vacuo. The crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield a colorless oil that crystallized to yield D11 (0.267 g, 56%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C(Cl)Cl>[C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCn1ccnc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1-c1ccccc1)c1ccco1

Procedure:
A mixture of 2.0 g. of 2-phenyl-1H-imidazole-1-propanamine, 50 ml. of methylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0 ml. of 2-furoyl chloride was added. The mixture was stirred for eighteen hours, methylene chloride was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The desired product was obtained as an oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[O:36]=[C:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17]([N:45]3[CH2:44][CH2:43][CH:42]([N:38]4[CH2:39][CH2:40][CH2:41][C:37]4=[O:36])[CH2:47][CH2:46]3)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Yield: 8 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (51.5 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (50.5 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.2 mg, 8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[C:9]1[N:13]2[CH:14]=[C:15](F)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.[NH2:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:23]([OH:30])[CH2:22][CH2:21]1.[H-].[Na+].N>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:30][C@H:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([NH2:19])[CH2:21][CH2:22]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: CN1CCN(C)C(c2nnc3ccc(F)cn23)C1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C)C(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of Intermediate 86c (100 mg, 0.40 mmol) and Intermediate A (79 mg, 0.40 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 56 mg, 1.4 mmol) portion-wise. The mixture was stirred at 60° C. for 1.5 h then allowed to cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL) then applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (104 mg, 66%). LCMS (Method 4): Rt 0.26, m/z 393 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[CH:7]=3)=[CH:4][C:3]=1[F:21].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Cl:22])=[CH:4][C:3]=1[F:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)c(Cl)c1C2
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(Cl)=C1c1cc(F)c(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 80.1 %

Procedure:
A solution of 7-amino-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.054 g, 0.175 mmol) in anhydrous N,N-dimethylformamide (0.35 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, and treated with N-chlorosuccinimide (0.024 g, 0.18 mmol). The mixture was stirred at room temperature for 18.5 hours and then heated in an oil bath at 35° C. for 3 hours. The reaction mixture was partitioned between EtOAc and water, and the organic phase was dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC on a YMC-Pak ODS column (2×10 cm), eluting with 0.1% TFA in 10–100% MeCN/H2O (15 min gradient) at a 20 mL/min flow rate. The product-containing fractions (UV detection at 350 nm) were diluted with EtOAc, washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and evaporated under vacuum. The residual film was triturated with hexanes and the solid residue was dried under a N2 stream to afford 7-amino-9a-butyl-4,8-dichloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (48 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[F-].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)C)[C-]1C=CC=C1)(C)C.[C-]1(P(C(C)C)C(C)C)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:25]1[CH:26]=[CH:27][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1I
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 4-cyano-3-iodo-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester (0.136 mmol) with 4-t-butyl-phenyl boronic acid (0.163 mmol), palladium acetate (0.027 mmol), 1,1′-Bis(di-i-propylphosphino)ferrocene (0.027 mmol), and potassium fluoride in DME at room temperature. Stirred at room temperature for 17 hours. Concentrated reaction in vacuo and purified by radial chromatography eluting with hexanes/methylene chloride to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.41 (q, 4H, J=21.7 Hz), 4.26 (q, 2H, J=7.0 Hz), 1.37 (s, 9H) and 1.21 (t, 3H, J=7.3 Hz), 19F NMR (CDCl3) δ—57.2 ppm (s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[CH:13]=1>>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:14]2[CH:13]=[C:12]([CH2:11][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH:17]=[CH:16][N:15]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: NC(=O)C1CCNCC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(C(N)=O)CC3)ccn2)cc(OC)c1OC

Procedure:
Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) were condensed by the same method as described in Example 2 to give the title compound as white needles.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>CN1CCCC1=O>[O:24]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1=[O:25]
Reactant: O=C(O)CCCCCCC/C=C\CCCCCCBr
Agent: O=C([O-])[O-]
Agent: O=C1CCCCCCC/C=C\CCCCCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCCCCC=CCCCCCCO1

Procedure:
40 g (0.29 mol) of potassium carbonate were suspended in finely pulverized form in 600 mg of N-methylpyrrolidone. 49 g (0.147 mol) of Z-16-bromohexadec-9-enoic acid in 300 ml of N-methylpyrrolidone were added dropwise within 6 hours. A standard work up was effected; bulb-tube distillation and recrystallization gave 19 g (51%) of 10Z-oxacydoheptadec-10-en-2-one were obtained having the following characteristics: Z/E=98/2;
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:16][O:15][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([NH2:14])=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(N)c2sc(N)nc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a suspension of 4.28 g (16.9 mmol) (7-amino-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 100 ml dioxane and 50 ml ethylene glycol was added 100 ml 5 N NaOH and the mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue diluted with 300 ml tetrahydrofuran and stirred for 10 minutes. The mixture was filtered and the filtrate concentrated in vactio. The residue was triturated in ether to afford 2.73 g (83%) 4-methoxy-benzothiazole-2,7-diamine as a brown solid. ES-MS m/e (%): 196 (M+H+, 100). b) 4-Methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])[CH:38]=[CH:39][C:40]=2[O:46][C:47](=[O:49])[CH3:48])[CH:7]=[CH:6][N:5]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccnc(Cl)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(Cl)c3)c2)=C(C)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
4-Amino-2-chloropyridine (0.103 g, 1.802 mmol), triethylamine (0.0812 g, 0.802 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.136 g, 0.802 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred in an oil bath at 50° C. for 8 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 (chloroform:methanol=10:1) to obtain the titled compound (0.078 g, 0.161 mmol, 30%).
Reaction SMILES: COC(=O)[C@@H](NC([C@@H]1CC2C=C3C(O[C@H](C4C=CC(O)=CC=4)C(=O)N3C)=CC=2CN1[C@H](C1C=CC=CC=1)CC)=O)CC1C=CC(C2C=CC(OC)=CC=2)=CC=1.C[O:57][C:58](=[O:119])[C@@H:59]([NH:75][C:76]([C@@H:78]1[CH2:91][C:90]2[CH:89]=[C:88]3[C:83]([O:84][C@H:85]([C:94]4[CH:99]=[CH:98][C:97]([O:100][CH2:101][C:102]5[CH:107]=[CH:106][C:105]([Cl:108])=[C:104]([Cl:109])[CH:103]=5)=[CH:96][CH:95]=4)[C:86](=[O:93])[N:87]3[CH3:92])=[CH:82][C:81]=2[CH2:80][N:79]1[C@H:110]([C:113]1[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=1)[CH2:111][CH3:112])=[O:77])[CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)=[CH:63][CH:62]=1>>[Cl:109][C:104]1[CH:103]=[C:102]([CH:107]=[CH:106][C:105]=1[Cl:108])[CH2:101][O:100][C:97]1[CH:98]=[CH:99][C:94]([C@H:85]2[O:84][C:83]3[C:88](=[CH:89][C:90]4[CH2:91][C@@H:78]([C:76]([NH:75][C@@H:59]([CH2:60][C:61]5[CH:66]=[CH:65][C:64]([C:67]6[CH:68]=[CH:69][C:70]([O:73][CH3:74])=[CH:71][CH:72]=6)=[CH:63][CH:62]=5)[C:58]([OH:119])=[O:57])=[O:77])[N:79]([C@H:110]([C:113]5[CH:114]=[CH:115][CH:116]=[CH:117][CH:118]=5)[CH2:111][CH3:112])[CH2:80][C:81]=4[CH:82]=3)[N:87]([CH3:92])[C:86]2=[O:93])=[CH:95][CH:96]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Yield: 92.1 %

Procedure:
(S)-2-{[(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester was converted to (S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (64 mg) using general procedure K. This ester upon hydrolysis furnished title compound (58 mg) LCMS (m/z): 884.
Reaction SMILES: [Cl-].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][N+:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[C:17]([CH3:20])=[CH:18][S:19][C:9]=12.[CH3:30][O-:31].[Na+]>CO>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:6]([CH:5]=[C:4]([C:3]([F:29])([F:28])[F:2])[CH:23]=1)[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10](/[C:17](/[CH3:20])=[CH:18]\[S:19][CH3:9])[C:30]1=[O:31]
Reactant: C[O-]
Reactant: Cc1csc2n1c1ccccc1[n+]2Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Yield: 74.8 %

Procedure:
285 mg of 9-[3,5-bis(trifluoromethyl)benzyl]-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride (0.632 mmol) were solubilised in methanol (40 mL), then 274 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-[3,5-bis(trifluoromethyl)benzyl]-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a white powder (211 mg, 77%). Mp 148° C.; Rf=0.72 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=2.18 (3H, d, J=1.1, CH3), 2.26 (3H, s, SCH3), 5.20 (2H, brs, CH2), 6.31 (1H, q, J=1.1, H5), 6.82-7.15 (4H, m, Ar), 7.75 (3H, brs, Ar); 13C NMR (75 MHz, CDCl3) δ=16.79, 20.45, 43.95, 107.84, 109.41, 121.88, 121.88 (1C, sept, J=3), 122.00, 123.07 (2C, q, J=272), 126.34, 127.50 (2C, q, J=3), 127.94, 128.36, 128.78, 132.17 (2C, q, J=34), 139.07, 152.19; HRMS m/z C20H17F6N2OS [M+H]+ calcd: 447.0960, found: 447.0959.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:8][C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([CH:21]2[CH2:22][CH2:23]2)=[O:20])=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1
Temperature: 78 °C

Procedure:
A 250-mL, three-necked round bottom flask fitted with a nitrogen inlet, magnetic stir bar, thermocouple, and condenser was charged with (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (8.26 g, 21.12 mmol), ethanol (82 mL), and half-saturated sodium bicarbonate (82 mL, 422 mmol). The reaction mixture was heated to 78° C. for 3 h and then cooled to rt. The ethanol was removed under reduced pressure, and the resulting solution was extracted with dichloromethane (2×125 mL). The combined organic layers were concentrated under reduced pressure. The crude product was diluted with 2-methyltetrahydrofuran (100 mL), and the resulting solution concentrated to remove trace water. This afforded (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (6.25 g, 100%) as an oil, which was used as is for the next step. MS (ESI, pos. ion) m/z 296. [M+1]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1(/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][CH2:38][S:37][CH2:36][CH2:35][NH:34][C:23](=[O:25])/[CH:22]=[CH:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCSCCN
Reactant: O=C(O)/C=C/C=C/c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCSCCNC(=O)/C=C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1,1′-Carbonyldiimidazole (0.36 g, 2.2 mmol) was added to a solution of 5-phenyl-penta-2E,4E-dienoic acid (1/1) (0.35 g, 2 mmol) in dry tetrahydrofuran (10 ml) and the obtained mixture was stirred for 1 hour at ambient temperature. To the mixture triethylamine (0.30 g 3.0 mmol) and methyl 3-(2-amino-ethylsulfanyl)-propionate hydrochloride (2e) (2.2 mmol) were added and the resultant suspension was stirred for 6 hours at ambient temperature. The solvent was removed under reduced pressure, to the residue water (15 ml) was added and the precipitate was filtered off, washed with water and dried, to give the title product. Yield 67%, m.p. 58-60° C. 1H NMR (90 MHz, DMSO-d6) δ: 2.54-2.89 (6H, m, CH2); 2.96-3.45 (2H, m, CH2); 3.61 (3H, s, CH3); 6.14 (1H, d, J=14.5 Hz, CH); 6.81-7.16 (2H, m, CH—CH); 7.11-7.69 (6H, m, C6H5, CH); 8.18 (1H, t, J=5.4 Hz, NH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH2:28][C:29]#[N:30])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH2:32]1[CH:34]([CH:35](O)C#N)[CH2:33]1.N1CCCCC1.O>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][NH:26][C:27](=[O:31])[C:28]([C:29]#[N:30])=[CH:35][CH:34]3[CH2:32][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: N#CC(O)C1CC1
Solvent: CO
Solvent: C1CCNCC1
Solvent: O
Product: N#CC(=CC1CC1)C(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Yield: 32.2 %

Procedure:
A solution of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyanoacetamide (90 mg, 0.22 mole), cyclopropylcarboxaldehyde (18 mg, 0.26 mmole) and piperidine (22 mg, 0.26 mmole) in MeOH (5 mL) was stirred for 3 hr at room temperature. Then water was added and extracted with ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (3% MeOH/DCM) to provide 39 mg (38% yield) of the title compound as a white solid. LCMS m/z 466 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:18][CH2:19][OH:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
tert-Butyl bromoacetate (32.3 ml; 0.2 mol) is slowly added dropwise, while cooling in ice, to a solution of N-benzylethanolamine (30.2 g; 0.2 mol) and triethylamine (27.9 ml; 0.2 mol) in anhydrous N,N-dimethylformamide (200 ml). The mixture is stirred at room temperature for 22 h and is then concentrated in vacuo. The residue is subsequently distilled repeatedly with toluene. The resulting oil is taken up in dichloromethane (400 ml) and extracted twice by shaking with water (160 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated. Yield: 47.8 g (90%), colourless oil.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:49]([N:53]=[C:54]=[O:55])[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:49]([NH:53][C:54]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:55])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCN=C=O
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l DIPEA and 25 l butyl isocyanate. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=637.