Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH2:2]([C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20](F)[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1)[CH3:3].[NH:26]1[CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[I-:1].[N:26]1([C:20]2[CH:19]=[CH:18][C:17]3[N:16]4[C:9]5[CH:8]=[CH:7][C:12]6[CH:13]=[C:4]([CH2:2][CH3:3])[CH:5]=[CH:6][C:11]=6[N+:10]=5[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]=3[CH:21]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: CCc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: CCc1ccc2c(ccc3n4c(ccc5cc(N6CCC6)ccc54)c[n+]23)c1
Reaction time: 168 h

Procedure:
A stirred mixture of 2.21 g. of 3-ethyl-10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 15 ml. of dimethylformamide and 1.0 ml. of azetidine is heated at 72° C. for 3 days in a pressure vessel, then cooled, treated with 0.5 ml. of azetidine and allowed to stand at 20°-25° C. for 7 days, with occasional agitation. The resulting precipitate of 10-(1-azetidinyl)-3-ethylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. 270°-275° C., after crystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(S(C2[C:54]3[C:53]4[C:48](=CC=CC=4)[CH:47]([CH:55]4CN(CCNC(=O)C)CC[N:56]4[C:67]4[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=4)NC=3C=CC=2)(=O)=O)C=CC=1Cl>>[N:56]1([CH:67]2[CH2:68][CH2:69][N:70]([CH2:17][CH2:18][CH2:13][NH:12][C:27](=[O:29])[CH2:26][CH:25]3[C:20]4[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:71][CH2:72]2)[CH2:55][CH2:47][CH2:48][CH2:53][CH2:54]1
Reactant: CC(=O)NCCN1CCN(c2ccncc2)C(C2Nc3cccc(S(=O)(=O)c4ccc(Cl)c(Cl)c4)c3-c3ccccc32)C1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCCN1CCC(N2CCCCC2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 3-[1,4′]bipiperidinyl-1′-yl)-propylamine trihydrochloride (Reference Example 3) according to the method described in Example 1e. MS (EI) 655.68 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)[NH2:21]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccccc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)phenyl-amine and hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH2:12][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][C:11]3([O:10][N:9]=[C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:12]3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Clc1cccnc1C1=NOC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2ncccc2Cl)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 83 %

Procedure:
Compound K (0.130 g, 0.451 mmol) was dissolved in toluene (15 ml) and triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.08 ml, 0.451 mmol) were successively added. The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling of the reaction mixture to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc1:1), the product was obtained in a yield of 83% (0.160 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=2)[CH:21]=[N:20]1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:28][C:25]3[CH:26]=[C:27]4[C:22]([CH:21]=[N:20][NH:19]4)=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc2cn[nH]c2c1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc3cn[nH]c3c2)nc(N)n1
Yield: 65 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 1H-indazol-6-ylamine provided the title compound (65% yield). 1H NMR (DMSO-d6) δ 1.34 (t, 3H, J=6.9 Hz, CH3), 4.13 (q, 2H, J=6.9 Hz, CH2), 6.26 (s, 2H, NH2), 6.85 (s, 1H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.30 (d, 1H, J=8.6 Hz, Ar), 7.41 (dd, 1H, J-8.9 Hz, 2.7 Hz, Ar), 7.65 (d, 1H, J=8.9 Hz, Ar), 7.95-7.97 (m, 3H, Ar), 9.27 (s, 1H, NH), 12.80 (s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][CH2:7][O:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BrH:11]>C(O)(=O)C>[Br:11][CH2:7][CH2:6][CH2:5][CH:4]([C:9](=[O:8])[CH3:10])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)OCCC1
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)C(CCCBr)C(C)=O

Procedure:
35.0 g. (0.25 mole) of 5-acetyl-6-methyl -3,4-dihydro-2H-pyrane prepared according to Example 21 are added dropwise into 250 ml. of a 33% solution of of hydrogen bromide in acetic acid, at room temperature, under stirring. The mixture is refluxed for 4 hours, with stirring. After cooling it is poured into 1 kg. of ice water and is then extracted with three 100-ml. portions of chloroform. The combined chloroform solution is washed subsequently with three 50-ml. portions of water, three 50-ml. portions of a 5% aqueous sodium bicarbonate solution and two 50-ml. portions of water, dried over solid anhydrous magnesium sulfate, decoloured with activated carbon and evaporated. The product obtained is purified by fractionated distillation on a short Wigreux column, in vacuum.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([NH2:11])[CH:8]=[CH:7]1)=[O:5].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:18]([NH:11][C@@H:9]1[CH2:10][C@H:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=[CH:8]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C=C[C@H](N)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 17 h
Yield: 105.3 %

Procedure:
Methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (5.50 g) was suspended in methylene chloride (60 mL), to which triphenylmethyl chloride (9.06 g, 0.0325 mol) was added. The mixture was then cooled to 0° C. Triethylamine (10.8 mL, 0.0774 mol) was then added dropwise keeping the temperature less than 10° C. Upon completion of addition, the mixture was allowed to warm to 20-25° C. The mixture was left to stir at 20-25° C. for 17 hours. The mixture was then washed with water (3×50 mL). The aqueous washes were combined and extracted with DCM (50 mL). The organics were combined and washed with brine (20 mL) and the solvent was removed under reduced pressure to afford the title compound as a brown oil (12.5 g) which was used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.58 (m, 6H), 7.27 (m, 6H), 7.18 (m, 3H), 5.57 (m, 1H), 4.93 (m, 1H), 3.76 (m, 1H), 3.65 (s, 3H), 3.18 (m, 1H), 2.11 (m, 1H), 1.90 (m, 1H) and 1.53 (m, 1H).
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: BrBr
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.3 g, 6.72 mmol) in MeOH (80 mL) was treated with two drops of HBr (48%), followed by bromine (0.4 mL, 7.73 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (2.5 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (85:15) gave 21-Bromo-3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.II.FC(F)(F)C(O[I:37](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([I:37])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 3,5-bis (methoxymethoxy)-2-(4-methoxybenzoyl)phenylacetate (0.75 g, 1.9 mmol) obtained in Example 134, Step 2 was dissolved in dichloromethane (20 mL). The resulting solution was cooled to −30° C., and iodine (0.47 g, 1.9 mmol) and [bis(trifluoroacetoxy)iodo]benzene (0.8 g, 1.9 mmol) were successively added thereto in an atmosphere of argon, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate, and the mixture was further stirred for one hour, while the temperature was raised to room temperature. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting, residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain methyl 3,5-bis(methoxymethoxy)-2-iodo-6-(4-methoxybenzoyl)phenylacetate (0.95 g, 96%).
Reaction SMILES: ClC1C(C[N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:20]N.CO>C(Cl)Cl>[C:10]1(=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[NH:9][NH:20]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl
Reactant: NN
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH][nH]c(=O)c2ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0 g, 36.5 mmol) in anhydrous CH2Cl2 (200 mL) was charged with hydrazine (2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N2 atmosphere. After 2.5 h, MeOH (30 mL) was added and the reaction was heated until the solution was homogenous. The reaction mixture was allowed to stir for 19 h. The white ppt that had formed (2,3-dihydrophthalazine-1,4-dione byproduct), was filtered off and washed several times with ether. The clear filtrate was concentrated in vacuo and the concentrate was dissolved in EtOAc and filtered again to remove white ppt. All solvent was removed, giving a yellow oil, which was dissolved into EtOAc and ether and charged with HCl (g). The title compound, a pale yellow solid, instantly precipitated. The title compound was dried in a 40° C. oven for 72 h, affording the title compound, as a dark yellow solid; 1H NMR (400 MHz, CD3OD) δ 4.55 (2 H, s), 8.27 (1 H, d, J=2.52 Hz), 8.54 (1 H, d, J=2.56 Hz); MS (ES+): #m/z 143.96/145.96 (100/60) [MH+]; HPLC: tR=0.41 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11](O)([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@:11]2([CH3:45])[O:8][C:7](=[C:9]([CH3:47])[CH2:10]2)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 63.7 %

Procedure:
Glacial acetic acid solution of erythromycin (12.4 g) was stirred at room temperature for 2 hours, added slowly aqueous sodium hydrogen carbonate and neutralized. The reaction mixture was extracted with chloroform, dehydrated the organic layer with mirabilite, filtered off the mirabilite and removed the solvent by distillation to obtain crude substance. The crude substance was purified with silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM201 (7.7 g). Subsequently, potassium carbonate (1.4 g) was added to the methanol solution of EM201 (7.6 g) and refluxed for 2 hours. After distilled off the solvent, the residue was dissolved in aqueous sodium hydrogen carbonate and extracted with chloroform. The mixture was dehydrated with mirabilite, filtered and removed the mirabilite, then the obtained crude substance was purified by silicagel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM701 (5.9 g, white powder).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH3:18])[CH:3]=1.C(=O)(O)[O-].[Na+].[NH3:24]>O1CCCC1>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11]([NH2:24])(=[O:13])=[O:12])[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH3:18])[CH:3]=1
Reactant: N
Reactant: Cc1cc(C)c(C(=O)O)c(S(=O)(=O)Cl)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)O)c(S(N)(=O)=O)c1C(=O)O
Reaction time: 2 h

Procedure:
To a mixture of 5 g dimethyl 2-(chlorosulfonyl)-1,3-benzenedicarboxylic acid and 1.4 g sodium bicarbonate in 25 ml tetrahydrofuran (dried over alumina) at 0°-5° was added, dropwise, a solution of 0.4 ml ammonia in 5 ml dry tetrahydrofuran. After stirring for 2 hours, the solution was evaporated, the resulting solid was washed with methylene chloride, then with water to give 2.4 g, m.p. 169° of dimethyl 2-(aminosulfonyl)-1,3-benzenedicarboxylic acid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
NaOH 4N (20 mL) was added to a solution of (trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate B, 4 g, 0.0149 mol), in Methanol (40 mL) and stirred at rt for 2 h. After completion of reaction, checked by TLC, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with HCl 4 N solution, the solid formed was filtered and dried to get (trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72%), as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:27])[CH:18](OC(C)(C)C)N(C)C>CN(C=O)C>[Si:1]([O:8][CH2:9][CH2:10]/[C:11](=[CH:16]\[N:17]([CH3:27])[CH3:18])/[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/N(C)C)CCO[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 87 %

Procedure:
A mixture of methyl 4-[tert-butyl(dimethyl)silyl]oxybutanoate (6.8 g, 29.31 mmol) and N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (5.1 g, 29.31 mmol) in DMF (14 mL) in sealed tube was heated to 100° C. overnight. Added water to the mixture at 0° C. and extracted with ethyl acetate twice. The organic phase was separated and washed with water (2×) and brine and dried with anhydrous Na2SO4. The organic phase was concentrated to give the title compound (7.33 g, 91%). [M+H] Calc'd for C14H29NO3Si, 288; Found, 288.
Reaction SMILES: N=[S:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].O.OP(O)(O)=O>CO>[C:13]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[C:25]([NH:26][C:3]2[S:2][C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc2c(c1)S(=N)C=N2
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: COc1ccc2nc(Nc3cccnc3Oc3ccccc3C(C)(C)C)sc2c1
Temperature: 25 °C

Procedure:
100 mg (0.38 mmol) of 1-imino-6-methoxybenzothiazole and 1b were heated under N2 atmosphere at 220° C. for 30 min, in a similar manner to 234a. After cooling to rt, the reaction mixture was suspended in MeOH and the side product bis(6-methoxybenzo[d]thiazol-2-yl)amine (46.3 mg) was eliminated by filtration. The mother liquors were purified by preparative HPLC to yield Example 233. tR=7.861 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna 4.6×50 mm; flow rate 2.5 mL/mn; detection at 220 nM; Gradient elation 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4 & B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C23H24N3O2S [M+H]+ 406.1589. found 406.1576.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=[O:8])=[O:7].C([NH:50][C:51](N1C=CC=N1)=[N:52]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:18]([S:17][CH2:16][C:12]3[C:11]([F:42])=[CH:10][C:9]([S:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([NH2:52])=[NH:50])(=[O:7])=[O:8])=[CH:14][C:13]=3[F:15])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCN)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCNC(=N)N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A solution of N-(3-aminopropyl)-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonamide (172 mg, 0.27 mmol), N,N′-di-Boc-1H-pyrazole-1-carboxamidine (100 mg, 0.32 mmol) and Et3N (190 μL, 1.35 mmol) in MeOH (10 mL) was stirred at 25° C. for 18 h. The reaction mixture was concentrated and reconstituted in EtOAc. The organic layer was washed with 1N HCl (3×5 mL), satd NaHCO3 (5 mL), dried over Na2SO4 and concentrated to a colorless oil. To the oil was added 4N HCl in dioxane (10 mL) at 25° C. and stirred for 18 h. Upon completion, the reaction mixture was concentrated and purified by preparatory HPLC (MeCN/H2O with 0.1% TFA, 10-99%) to give the title product (54 mg, 28% yield) as white solid. 1H NMR (400 MHz, MeOD) δ 7.99 (s, 1H), 7.51 (s, 2H), 7.37 (s, 1H), 7.28 (d, J=5.7 Hz, 1H), 6.98 (s, 2H), 6.62 (s, 2H), 6.56 (s, 2H), 4.14 (s, 2H), 3.73 (s, 3H), 3.70-3.54 (m, 3H), 3.30-3.21 (m, 2H), 3.00 (s, 2H), 1.80 (s, 2H), 1.63 (s, 6H); MS (EI) m/z 681 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:27]1([CH2:33][C:34](OC)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH2:15][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
4-Acetyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) was dissolved in anhydrous THF (6 mL) and cooled to 0° C. To this was added a solution of lithium hexamethyldisilazane (1.0M in hexanes; 4.84 mL). This was left to stir at 0° C. for 10 minutes before addition of a THF solution (2 mL) of methyl phenylacetate (0.661 g). The reaction mixture was left to stir for a total of 4 hours before being quenched by the addition of 1M aqueous HCl (50 mL). The reaction mixture was extracted with Et2O (3×75 mL) then the combined organic extracts were dried over magnesium sulfate and filtered. Evaporation of solvents under reduced pressure gave a thick yellow oil which was purified by column chromatography on silica gel, using an increasingly polar gradient of Et2O in DCM as eluent. Evaporation of solvents under reduced pressure gave the desired 4-(3-oxo-4-phenyl-butyryl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.225 g); NMR (CDCl3): 1.45 (s, 9H), 1.54 (m, 2H), 1.76 (d, 2H), 2.28 (tt, 1H), 2.71 (br t, 2H), 3.61 (s, 2H), 4.12 (br d, 2H), 5.44 (s, 1H), 7.12-7.36 (m, 5H), 15.30 (s, 1H); MS: 344 (M−1−).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:11][C@H:10]([NH2:12])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3].[F:19][C:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:2]([N:5]1[CH2:11][C@H:10]([NH:12][C:21](=[O:22])[C:20]([F:19])([CH3:35])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:32])[F:31])=[O:25])[C:9](=[O:13])[N:8]([CH3:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N1C[C@H](N)C(=O)N(C)c2ccccc21
Reactant: CC(F)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: Cl
Product: CC(=O)N1C[C@H](NC(=O)C(C)(F)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-5-acetyl-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and 2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white foam;