Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH2:71])=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH:71][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CC1CC1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylacetic acid (0.300 g, 3.00 mmol), HATU (1.14 g, 3.00 mmol), and diisopropylethylamine (0.627 ml, 3.60 mmol) were added sequentially to a solution of 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.78 g, 3.00 mmol) in DMF (50 ml) at 25° C. The reaction mixture was stirred for 1.5 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (125 ml) and EtOAc (2×150 ml). The combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 3-[1-benzenesulfonyl-5-(2-cyclopropyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a brown foam. LCMS (Method G, ESI): RT=1.24 min, m+H=676.4. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[C:8]([CH:11]=1)[C:9]#[N:10])([CH3:3])[CH3:2].[Sn](Cl)[Cl:23]>Cl.C(O)C>[ClH:23].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=[C:9]([NH2:10])[C:8]=2[CH:11]=1)([CH3:3])[CH3:2]
Reactant: Cl[Sn]Cl
Reactant: CC(C)c1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N)=Nc1ccccc1N2
Temperature: 86 °C

Procedure:
Combine 5-isopropyl-2-(2-nitro-phenylamino)-benzonitrile (4.54 g, 16.1 mmol) and tin (II) chloride (10.92 g, 48.4 mmol) in 65.0 mL of 5N HCl solution and 65.0 mL of ethanol. Heat this mixture at 86° C. for 18 hours. Chilling the mixture precipitates the title compound as 4.22 g of a yellow solid: mp>250° C.; mass spectrum (ion spray): m/z=252 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.[CH2:22]([N:29]1[C:37]2[C:32](=[C:33]([NH:38][C:39]([C:41]3[N:45]4[CH:46]=[CH:47][C:48](Br)=[CH:49][C:44]4=[N:43][CH:42]=3)=[O:40])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O.CN(C=O)C.CC#N>O.CO.C(Cl)Cl.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>[CH2:22]([N:29]1[C:37]2[C:32](=[C:33]([NH:38][C:39]([C:41]3[N:45]4[CH:46]=[CH:47][C:48]([C:9]5[CH:10]=[N:11][NH:12][CH:13]=5)=[CH:49][C:44]4=[N:43][CH:42]=3)=[O:40])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(Br)ccn12
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(-c3cn[nH]c3)ccn12
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A dried round bottom flask equipped with a reflux condenser and a nitrogen line was charged with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (16.7 mg, 0.057 mmol), N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide (23 mg, 0.052 mmol), Pd(PPh3)4 (3.0 mg, 0.003 mmol), and potassium carbonate (36 mg, 0.26 mmol). To the flask was added a water/DMF/CH3CN mixture (1:1:4.5; 0.1:0.1:0.6 mL), and the reaction mixture was degassed under nitrogen and heated at 80° C. for 6 hours. The cooled reaction mixture was diluted with water and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as eluent to afford 13.9 mg of the desired product as a yellow solid. MS (ES+APCI) m/z=534 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2cccc(F)c2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1cccc(F)c1
Yield: 92 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(3-fluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one to obtain the title compound (92%).
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])[CH:9]=[CH:10][C:11]=1[Cl:12])([O-:5])=[O:4]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[N+:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:14])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccn2)ccc1Cl
Agent: [Cr+6]
Agent: Cl
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccn1
Temperature: 0 °C

Procedure:
A solution of 27 g. (0.27 mol) of chromium trioxide in 250 ml. of water was added to a solution of 80 g. (0.266 mol) of 3-nitro-4-chlorophenyl-2-pyridyl methanol hydrochloride in 800 ml. of 75% acetic acid at 45° C. and the mixture was heated to 75° C. for 1 hr. The resulting dark green solution was poured into 3 liters of ice-water. The resulting product was filtered off, washed with water, dissolved in methylene chloride, dried with sodium sulfate and concentrated in vacuo to yield 2-(3-nitro-4-chlorobenzoyl)pyridine as white microneedles, mp. 98° -99° C. (cyclohexane).
Reaction SMILES: ClN1[C:7](=[O:8])[N:6]([Cl:9])[C:5](=O)N(Cl)C1=O.[Cl:13][CH2:14][CH:15]1[O:19]C(=O)NC1>C(Cl)Cl>[Cl:9][N:6]1[CH2:5][CH:15]([CH2:14][Cl:13])[O:19][C:7]1=[O:8]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: O=C1NCC(CCl)O1
Solvent: ClCCl
Product: O=C1OC(CCl)CN1Cl

Procedure:
8.4 grams (0.036 moles) trichloroisocyanuric acid were dissolved in dried methylene chloride. To this suspension were added 5 grams (0.036 moles) 5-Chloromethyl-2-oxazolidinone. The mixture was stirred for several hours before filtering to remove solids. The methylene chloride layer was rotovaped to recover the product, a yellow liquid Proton NMR Data: δ3.7 (m, 4 protons), 4.8(m, 1 proton). Elemental analysis Chlorine found 39.66 (theory 41.7).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3ccc(Br)cc32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromoindole (J. Org. Chem. 1986, 51, 5106) (3.00 g, 15.3 mmol) in DMF (65 mL) was treated with NaH (734 mg of a 60% suspension in mineral oil, 18.4 mmol). After 30 min, 4-fluorobenzyl bromide (1.90 mL, 15.3 mmol) was added. When starting material was consumed, the reaction mixture was poured into 1N HCl and extracted with EtOAc (3×), the combined organic layers were dried (MgSO4) and concentrated. Chromatography of the residue (4:1/hexanes:EtOAc) provided the product.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:18][C:19]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:21][C:20]=1[CH:30]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[OH:31].C(N(CC)CC)C>O1CCCC1>[Br:18][C:19]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:21][C:20]=1[C:30]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: COc1ccc2oc(C(O)C3CCCCC3)c(Br)c2c1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2oc(C(=O)C3CCCCC3)c(Br)c2c1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a mixture of dimethyl sulfoxide (831 mL) and tetrahydrofuran (20 mL) was added trifluoroacetic acid anhydride (1.63 mL) at −78° C., and the mixture was stirred for 30 min, and a solution (20 mL) of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol (2.03 g) synthesized in Example A102(4) in tetrahydrofuran was added. The reaction mixture was stirred under argon atmosphere at −78° C. for 1 hr, triethylamine (3.33 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (1.52 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:4][C:5]([NH:7][C@@H:8]([C:32]([NH:34][CH2:35][C:36]([O:38]C)=[O:37])=[O:33])[C:9]([S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:11])[CH3:10])=[O:6])[CH3:3].[OH-].[Na+].OS([O-])(=O)=O.[K+]>CO>[CH3:3][C:2]([CH3:40])([O:4][C:5]([NH:7][C@@H:8]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])[C:9]([S:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:10])[CH3:11])=[O:6])[CH3:1]
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCC(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a MeOH (160 mL) solution of the product of Example 32 (22.2 g, 0.039 mol) was added dropwise to vigorously-stirred 80 mL of 1.0 N NaOH. After 2 hours, the pH of the homogenous solution was adjusted to pH 2 with 1.0 M KHSO4. The white precipitate generated was filtered, washed with water, dried in the vacuum oven at 50° C. over night and dissolved in 150 mL of CH2Cl2. This solution was filtered before the solvent volume was reduced by rotary evaporation, and the product precipitated with n-hexane. The white solid product was filtered, washed with hexane, and dried in vacuo. A crude 24.8 g (98% by HPLC) sample of the desired title material was isolated as a white solid, and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)cc(Cl)n1
Yield: 81.2 %

Procedure:
A solution of 2,6-dichloropyridin-4-amine 41.6.A (available from Aldrich) (3.10 g, 19.0 mmol) in 20% NaOMe/MeOH (15 mL) was refluxed for 72 hr. The reaction mixture was diluted with H2O (40 mL) and extracted with 30% iPrOH/CHCl3 (3×30 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL) and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave title product 41.6.B as white solid (2.45 g, 81.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.O.[C:8]([OH:12])(=[O:11])[CH:9]=[O:10].[OH-].[Na+].C>>[OH2:10].[OH:10][CH:9]([C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[C:8]([OH:12])=[O:11]
Reactant: O=CC(=O)O
Reactant: Nc1nccs1
Agent: N=c1[nH]ccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(C(O)C(=O)O)s1
Reaction time: 1.5 h

Procedure:
A mixture of 2-amino-1,3-thiazole, which can be represented as 2-imino-2,3-dihydro-1,3-thiazole, (36.3 g.), glyoxylic acid hydrate (50 g.) and 1 N sodium hydroxide (543 ml.) was stirred for 1.5 hours at 90° to 93° C. After the reaction, the reaction mixture was treated with an activated charcoal and then adjusted to pH 3. The mixture was allowed to stand overnight under ice-cooling. The precipitates were collected by filtration, washed with water and then dried to give 2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetic acid hydrate, which can be represented as 2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetic acid hydrate (48.1 g.), mp. 140° to 200° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH2:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH:32][S:12]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCCOc2ccc(Cl)cc2Cc2ccccc2)CCNS(=O)(=O)c2cc(Br)cc3cnccc23)cc1

Procedure:
Using a procedure analogous to Preparation 103, reaction of 7-bromo-isoquinoline -5-sulfonyl chloride with N1-[3-(2-benzyl-4-chloro-phenoxy)-propyl]-N1-[bis-(4-methoxy-phenyl)-methyl]-ethane-1,2-diamine provides the title compound as a foam. ESIMS: m/z 814[(M+H)+, 35Cl, 79Br], 816 [(M+H)+, 37Cl, 79Br or 35Cl, 81Br], 818 [(M+H)+, 37Cl, 81Br].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([O:19]CC)([O:16]CC)=[O:15])[C:5]=2[N:6]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([OH:19])([OH:16])=[O:15])[C:5]=2[N:6]=1
Reactant: CCOP(=O)(COc1cc(Br)cc2sc(N)nc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1nc2c(OCP(=O)(O)O)cc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole) in CH2Cl2 (4 mL) was treated with TMSBr (10 mmole) at 0° C. After stirred for 8 h at room temperature the reaction was evaporated to dryness and the residue was taken into water (5 mL). The resulting precipitate was collected via filtration and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (34.1) as white solid. mp>220° C.(dec.). Anal. Calcd. for C8H8N2O4PSBr: C, 28.34; H, 2.38; N, 8.26. Found: C, 28.32; H, 2.24; N, 8.06.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH3:22])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH3:22])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1
Reactant: COC(=O)c1coc(COc2cc(CN[C@H](C)c3cccc(Cl)c3)ccc2Cl)n1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(OCc2nc(C(=O)O)co2)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of (R)-methyl 2-((2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenoxy)methyl)oxazole-4-carboxylate 102 (69 mg, 159 μmol) in 2 mL of dry THF, was added potassium trimethylsilanolate (22 mg, 174 μmol). The solution was stirred at ambient temperature for 2 h. The reaction was concentrated and the resulting crude material was purified with reverse phase preparatory HPLC. The desired fractions were combined and lyophilized to give (R)-2-((2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenoxy)methyl)oxazole-4-carboxylic acid 103 (41 mg, 61% yield) as a white solid and as the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.68-1.74 (m, 3H) 4.02 (d, J=13.30 Hz, 1H) 4.20 (d, J=13.30 Hz, 1H) 4.48 (q, J=6.85 Hz, 1H) 5.34 (s, 2H) 7.04 (dd, J=8.22, 1.76 Hz, 1H) 7.33 (d, J=1.76 Hz, 1H) 7.43-7.52 (m, 4H) 7.56 (s, 1H) 8.60 (s, 1H). Mass spectrum: calculated for C20H18Cl2N2O4 421.3. found 422.4 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[N+:35]([O-])=O)[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]>C(O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:34]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of 3-methoxy-4-nitro-N-methyl-N-[4-methyl-2-[5-(4methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]benzamide (6.2 g) and iron powder (3.43 g) in a mixture of ethanol (65 ml) and ethyl acetate (6 ml) was refluxed for 2 hours. After being cooled to ambient temperature, the solution was filtered through a bed of Celite and the filtrate was evaporated in vacuo. The residue was diluted with ethyl acetate and the solution was washed with saturated sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]benzamide (4.7 g ).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([C:38]([O:40][CH3:41])=[O:39])=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:31]([C:38]([O:40][CH3:41])=[O:39])=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To 1 mL of an ethyl acetate solution containing 30 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 42 hours. The resulting solid was filtered to give 18 mg of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,2-dihydro-2-oxoquinoline-4-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[NH2:38]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][NH:37][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=1)=[O:8])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(NNC(=O)c2cccc(C#N)c2)cc1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
At 0° C., to a suspension of 3-cyanobenzoic acid (0.62 g, 4.2 mmol) in dichloromethane (15 mL) is added THE dropwise until the system became homogenous, which is followed by the addition of 1-hydroxybenzotriazole (0.57 g, 4.2 mmol) and dicyclohexylcarbodiimide (0.87 g, 4.2 mmol). The mixture is brought to room temperature slowly and stirred for 0.5 h. To the mixture, methyl 4-hydrazinobenzoate (0.63 g, 3.8 mmol) is added and the mixture is stirred for 2 hr. The precipitate is then removed by filtration and washed with dichloromethane. The filtrate is washed with water and brine, dried over anhydrous Na2SO4, which is discarded later. The crude product obtained after the removal of the solvent is separated by column chromatography (silica gel, 1:19 ethyl acetate-dichloromethane) to provide the intermediate, methyl 4-[2-(3-cyanobenzoyl)hydrazino]benzoate (0.68 g, 61%). MS (ES+) m/z: 296.