Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4](=[S:6])[NH2:5])#[N:2].N1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19](O)[CH3:20]>>[SH:6][C:4]1[N:5]=[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:14]2=[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:1]#[N:2]
Reactant: C1CCNCC1
Reactant: N#CC(=Cc1cccs1)C(N)=S
Reactant: CCO
Product: N#Cc1c(S)nc2c(c1-c1cccs1)CCCCC2
Temperature: 80 °C
Yield: 25 %

Procedure:
A mixture of 2-cyano-3-thien-2-ylprop-2-enethioamide (4.2 g, 21 mmol), cycloheptone (2.4 g, 21 mmol) and piperidine (1.8 g, 22 mmol) in ethanol (100 mL) was heated to 80° C. overnight. After removal of the solvent, the residue was treated with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The crude product, obtained after removal of the solvent, was purified by flash chromatography to afford 2-mercapto-4-thien-2-yl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile (1.6 g, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O-])=O.C1COCC1.Cl>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCc2cc(Cl)ccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2cc(Cl)ccc2N)cc1
Reaction time: 13 h
Yield: 100.4 %

Procedure:
A mixture of methyl 4-(2-nitro-5-chlorophenylmethoxy)benzoate (460 mg; prepared in Reference Example 9.), THF (10 ml), water (3 ml), 1 N HCl (0.4 ml) and iron powder (500 mg) was stirred for 13 hours. The reaction mixture was filtered. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (419 mg) having the following physical data.
Reaction SMILES: ClC(Cl)C.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][CH2:18][CH2:19][CH2:20][OH:21].[O-:22]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:18][CH2:19][CH2:20][OH:21])=[O:22]
Reactant: Cc1ccccc1-n1ccnc1SCCCO
Reactant: [O-]O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Solvent: CC(C)c1ccccc1
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.2 %

Procedure:
To 3 l of dichloroethane were added 123 g of 3-[1-(2-methylphenyl)-2-imidazolylthio]propanol, 414 g of L-(+)-diethyl tartarate and 120 g of a powder of Molecular Sieve 4A. The mixture was stirred at room temperature for 2 days. Thereto was added 142 g of titanium tetraisopropoxide. The mixture was stirred at room temperature for 30 minutes. Thereto was added 91 g of cumene hydroperoxide. The mixture was stirred at 5° C. for 24 hours. The reaction mixture per se was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=50/1). Recrystallization from methyl ethyl ketone was repeated to obtain 50 g of (S)-(+)-3-[1-(2-methylphenyl)2-imidazolylsulfinyl]propanol.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][N:8]([C:18](=[O:50])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39]C(OCC1C=CC=CC=1)=O)[NH:20][C@@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:52].CCOCC>C(O)(=O)C>[BrH:52].[BrH:52].[CH2:33]([O:32][C:30]([C@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:51])=[O:5])=[O:50])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
Nα -[1-(R)-Ethoxycarbonyl-3-phenylpropyl]-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester (1 g) is dissolved in 2 ml of acetic acid. To the solution, 8 ml of 25% hydrobromic acid solution in acetic acid is added, and the mixture is allowed to stand at room temperature for 30 minutes. On adding 200 ml of ether and 100 ml of petroleum forms. This is collected by filtration and recrystallized from a mixture of methanol and ethyl ether to give 0.8 g of Nα -[1-(R)-ethoxycarbonyl-3-phenylpropyl]L-lysyl-N-(indan-2-yl)glycine dihydrobromide melting at [α]D24 =-11.6° (c=1, methanol)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:20](Cl)[CH:21]=[CH2:22].[CH2:24](O)[CH2:25][CH3:26]>>[CH3:9][C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:15][CH:16]=1)([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][CH:21]=[CH2:22])=[CH:7][CH:6]=1)[CH3:10]
Reactant: C=CCCl
Reactant: CCCO
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1ccc(C(C)(C)c2ccc(OCC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bisphenol A (228 g), NaOH (82.5 g) and n-propanol (1 liter) are heated under reflux. After everything has gone into solution, 200 ml of allyl chloride are added slowly. After three hours, the mixture is virtually neutral. It is stirred for a further three hours, whilst boiling under reflux. After cooling to room temperature, the NaCl which has precipitated is filtered off and the n-propanol is distilled off. The crude diallyl ether of bisphenol A (308 g) which is thus obtained is taken up in methylene chloride and washed with water. After separating off the aqueous phase, the methylene chloride is distilled off again. The resulting pure diallyl ether of bisphenol A is dried over sodium sulphate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl.O>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:39]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:40])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)C1CCCC1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (962 mg, 2.066 mmol) synthesized in the same manner as in Example 1, cyclopentanecarboxylic acid (0.448 ml, 4.13 mmol), 2-chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) in methylene chloride was added triethylamine (1.267 ml, 9.09 mmol), and the mixture was stirred at room temperature for 1 hr. 2-Chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure basic silica gel column (hexane:ethyl acetate=1:3) and concentrated under reduced pressure to give the title compound (yield 261 mg, 22.49%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[CH3:2].Cl[C:19]1[N:20]=[N:21][CH:22]=[C:23](C#N)[CH:24]=1.C(=O)([O-])O.[Na+].[CH3:32][N:33]1C(=O)CCC1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[C:5]([CH:10]=1)[CH2:4][N:3]([C:22]1[N:21]=[N:20][C:19]([C:32]#[N:33])=[CH:24][CH:23]=1)[CH2:1][CH3:2]
Reactant: CN1CCCC1=O
Reactant: N#Cc1cnnc(Cl)c1
Reactant: CCNCc1cc(Cl)ccc1OCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(Cc1cc(Cl)ccc1OCC1CCC1)c1ccc(C#N)nn1

Procedure:
N-Ethyl 5-chloro-2-(cyclobutylmethoxy)benzylamine (2.1 g, 8.3 mmol) was coupled to the 3-chloro-5-cyanopyridazine (1.3 g, 8.25 mmol) with sodium hydrogen carbonate (0.71 g, 8.45 mmol) in NMP (10 ml) in a similar method to that of reference example 18. The title compound was purified by MPLC( dichloromethane, 1%MeOH/dichloromethane) (2.3 g, 78%) to give a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:3]1.C(Cl)(Cl)=[O:17].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH2:34]([Cl:36])Cl>>[Cl:36][CH2:34][CH2:5][CH:4]1[C:7]2=[N:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]2[C:1](=[O:17])[N:2]([CH3:6])[CH2:3]1
Reactant: ClCCl
Reactant: O=C(Cl)Cl
Reactant: CN1CCC(c2nc3ccccc3[nH]2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reaction time: 2 h

Procedure:
A solution of 4 g (0.02 mol) of 2-(1-methyl-3-pyrrolidinyl)-1H-benzimidazole in 100 mL of CH2Cl2 was added dropwise to a solution of 12.5 (0.025 mol) of 20% phosgene/toluene in 30 mL of CH2Cl2. The solution was stirred for 2 h, and 10 g (0.1 mol) of triethylamine was added dropwise. Stirring was continued for 2 h and the solution was extracted with dilute NaOH. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized twice from isopropyl ether. Yield 1.5 g (28%), mp 88°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:8]2[CH3:11])=[C:4](I)[CH:3]=1.[Cu][C:28]#[N:29].ClCCl.C(O)C>CN(C)C=O>[C:28]([C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:25])[N:7]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH:8]2[CH3:11])#[N:29]
Reactant: N#C[Cu]
Reactant: CC1c2cc(F)cc(I)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1c2cc(F)cc(C#N)c2C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
Tert-butyl 4-(6-fluoro-4-iodo-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-1-carboxylate (240 mg, 0.5 mmol) and copper(I) cyanide (67 mg, 0.75 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the resulting solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (174 mg, 93% yield).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH:27]([C:29]1[N:33]([CH3:34])[CH:32]=[C:31]([C:35]([O:37][CH3:38])=[O:36])[CH:30]=1)=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[C:31]([C:35]([O:37][CH3:38])=[O:36])[CH:30]=3)=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2csc3ccccc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 506.31 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl.CC[N:22]([CH2:25]C)CC.N.C1C[O:31]CC1>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:25]([NH2:22])=[O:31])[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: C1CCOC1
Reactant: NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N
Product: NC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg, 0.54 mmol) and Et3N (164 mg, 1.62 mmol) in dry THF (20 mL) was added (COCl2)3 (160 mg, 0.54 mmol) at rt. The reaction mixture was stirred at rt for 1 hour, and then a solution of NH3 in THF (4 N, 10 mL) was added drop-wise. The resulting mixture was stirred at rt for 5 hours, concentrated to dryness and purified by HPLC to give the title compound (140 mg, 69%). MS (ESI): mass calcd. for C13H18BrN3O3S, 375.03; m/z found, 376.0 [M+H]+.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:10][S:11][CH2:12][C:13]#[N:14].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:25][C:8]([F:7])([C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])[CH2:9][CH2:10][S:11]([CH2:12][C:13]#[N:14])=[O:1]
Reactant: N#CCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a suspension of 15.10 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 100 ml of water was added dropwise a solution of 4.77 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylthio)acetonitrile in 100 ml of methanol at −20° C. over 60 minutes under a nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction mixture was added 50 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 50 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 12.56 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile represented by the formula:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:3]1.[CH3:32][C:33]([CH3:35])=O.[C:36]([BH3-])#N.[Na+].C=O>C(Cl)Cl>[CH:33]([N:1]([CH3:36])[C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH2:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:3]1)([CH3:35])[CH3:32]
Reactant: CC(C)S(=O)(=O)C[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The entirety of benzyl benzyl (S)-1-((1S,2R,4R)-4-amino-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate prepared in Step 1 (1 eq) was dissolved in CH2Cl2 (20 mL). The resultant solution was charged with acetone (10 eq) and stirred at RT for 10 min before sodium cyanoborohydride (2 eq) was added in one portion. The reaction was stirred at RT for 10 h and then charged successively with formaldehyde (10 eq. in 37 wt % aq soln) and sodium cyanoborohydride (2 eq). The reaction was stirred for another 9 h at RT and then quenched with sat. NaHCO3. The aqueous mixture was extracted with EtOAc (200 mL, then 2×75 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. After the resulting oil stood, some paraformaldehyde-related products solidified; these were removed by dissolving the mixture in a minimal volume of EtOAc and filtering. Subsequent concentration provided benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=508.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:44]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([CH2:56][NH2:57])[CH2:53][C@H:52]1[C:58]([N:60]1[CH2:64][CH2:63][S:62][CH2:61]1)=[O:59])=[O:50])([CH3:47])([CH3:46])[CH3:45]>CN(C)C=O>[C:44]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([CH2:56][NH:57][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([O:12][CH3:13])=[O:11])[CH:3]=2)[CH2:53][C@H:52]1[C:58]([N:60]1[CH2:64][CH2:63][S:62][CH2:61]1)=[O:59])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)NC[C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of monomethyl isophthalate (226 mg, 1.26 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added 1-hydroxybenzotriazole monohydrate (204 mg, 1.51 mmol), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (288 mg, 1.51 mmol) and triethylamine (0.180 mL, 1.26 mmol). The mixture was stirred at room temperature for 30 minutes followed by the addition of a solution of Example 17D (380 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (2 mL). The mixture was allowed to stir at room temperature for 16 hours, concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and extracted with 1 M HCl (20 mL), saturated sodium bicarbonate (20 mL) and brine (20 mL) respectively. The organic layer was separated and dried (Na2SO4), filtered and concentrated to a light yellow oily solid which was chromatographed on a Biotage 40M with ethyl acetate to provide the titled compound. MS (APCI) m/e 478 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:11]([F:12])=[CH:10][C:9]([O:13]CC3C=CC(OC)=CC=3)=[CH:8][C:7]=2[F:23])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]([C:6]2[C:7]([F:23])=[CH:8][C:9]([OH:13])=[CH:10][C:11]=2[F:12])=[O:5])[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cc(F)c(C(=O)C3CC3)c(F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1c(F)cc(O)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclopropyl {2,6-difluoro-4-[(4-methoxybenzyl)oxy]phenyl}methanone (700 mg, 2.20 mmol) in DCM (10 ml) was added to TFA (3.0 mL) and the resulting solution stirred for 2 hour at RT. The material was concentrated under reduced pressure and the residue purified via flash column chromatography (80 g silica gel, ISCO, eluting with 30-100% ethyl acetate in hexane) to afford the title compound as an oil. 1H NMR (CDCl3): δ 8.20 (s, 2H), δ 2.43-2.38 (m, 1H), δ 1.35-1.28 (m, 2H), δ 1.10-1.03 (m, 2H). LC/MS 221 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5.0 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 4-(4-fluorophenyl)-piperazine in 30 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature around 90° C. for approximately 4 hours. After cooling to approximately 20° C., 25 cm3 of water were added to the reaction mixture. The insoluble material was filtered off and washed with 2 times 25 cm3 of water. After recrystallizing once from 150 cm3 of dimethylformamide, 7.6 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 318-9° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:13])[N:7]2[CH3:12].ClC([O:17][C:18](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([N:41]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[CH2:45][N:44]3[CH:52]=[CH:53][CH:54]=[C:43]3[CH2:42]2)=[O:40])=[CH:35][C:34]=1[CH3:55]>C1(C)C=CC=CC=1.C1COCC1>[CH:54]1[CH:53]=[CH:52][N:44]2[CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N:41]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:18]([N:4]4[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[F:1])[N:7]([CH3:12])[C:6](=[O:13])[CH2:5]4)=[O:17])=[C:34]([CH3:55])[CH:35]=3)=[O:40])[CH2:42][C:43]=12
Reactant: CN1C(=O)CNc2c(F)cccc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1CN
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1CNC(=O)N1CC(=O)N(C)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-fluoro-1-methyl-3,4-dihydro-1H-quinoxalin-2-one from Example 18A (72 mg, 0.40 mmol) in toluene (4.0 ml) were added trichloromethyl chloroformate (48 μl, 0.40 mmol), diisopropylethylamine (72 μl, 0.40 mmol) and a spatula full of activated carbon. The mixture was heated at reflux for 2 h. The mixture was cooled to room temperature, filtered through Celite® and evaporated. The residue was taken up in THF (3.0 ml) and added to a solution of (4-aminomethyl-3-methyl-phenyl)-(5H,11H-benzo[e]pyrrolo[ 1,2-a][1,4]diazepin-10-yl)methanone from Example G (119 mg, 0.36 mmol) in THF (5.0 ml) and diisopropylethylamine (72 μl, 0.40 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 1.5 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 85:15) to give a pale yellow solid; yield 112 mg, 58%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][OH:14]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: NCCO
Solvent: C1CCOC1
Product: COc1nc(NCCO)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and 2-amino ethanol (1.76 mL, 29.1 mmol) in THF (50 mL) was stirred for 18 h at rt. 2-Amino ethanol (2 mL) was added. The reaction mixture was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 3:2) to afford 4.08 g of the title compound. tR: 0.70 min (LC-MS 2); ESI-MS: 248.2 [M+H]+ (LC-MS 2); Rf: 0.06 (hexane/EtOAc 3:2).