Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]=1[CH2:39][NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.4 mL, 7 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g, 7 mmol) (60% in oil) and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (3.01 g, 7 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate (3.11 g, 88.9%) as crystals.
Reaction SMILES: [F:1][C:2]1([C:15]([O:17]CC)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:20](=[N:23]O)([NH2:22])[CH3:21].C[O-].[Na+]>O1CCCC1>[F:1][C:2]1([C:15]2[O:17][N:23]=[C:20]([CH3:21])[N:22]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1(F)CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(N)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2(F)CCCN(C(=O)OC(C)(C)C)C2)n1

Procedure:
The mixture of 1-tert-butyl 3-ethyl 3-fluoropiperidine-1,3-dicarboxylate 33 and 1a,b (0.8 g, 0.0029 mol) and acetamide oxime (0.54 g, 0.0073 mol) were dissolved in 30 mL tetrahydrofuran. Sodium methoxide (0.79 g, 0.0146 mol) was added and the mixture was heated at reflux for 1.75 hours. The mixture was concentrated and partitioned between water (25 mL) and ethyl acetate (1×100 mL). The aqueous layer was extracted with an additional 50 mL ethyl acetate. The combined organics were washed with 1×25 mL water, 1×40 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed to remove 1a,b with 15 g silica gel, 100% dichloromethane to 5% ethyl acetate/dichloromethane, to obtain 0.18 g of clear colorless oil. MS (ESI) m/z 324 [M+K]+. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.55-62 (m, 1H), 1.70-1.74 (d, 1H), 1.92-1.95 (m, 1H), 2.17 (m, 1H), 2.29-2.32 (m, 1H), 2.43 (s, 3H), 3.06-3.12 (m, 1H), 3.89-3.92 (m, 2H).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH2:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Yield: 89 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.9 g.), conc. hydrochloric acid (1.4 g.) and methanol (30 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.[CH3:36][N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39](O)=[O:40].C(Cl)CCl>C(Cl)Cl.N1C=CC=CC=1>[C:23]([N:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:39]([C@@H:38]3[CH2:42][CH2:43][CH2:44][N:37]3[CH3:36])=[O:40])=[CH:35][CH:34]=2)=[O:11])[CH:13]([CH3:33])[CH2:14]1)(=[O:25])[CH3:24]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1CC(C)N(C(=O)c2ccc(OCCCNC(=O)[C@@H]3CCCN3C)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (100 mg, 0.204 mmol) was dissolved in methylene chloride (2 mL) and pyridine (2 mL). N-methyl proline (33 mg, 0.255 mmol) and EDC (63 mg, 0.255 mmol) were added and the reaction was stirred for 1 hour. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate) to afford the product.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([C:40]=2[OH:41])=[CH:38][CH:37]=[C:36]([S:42]([NH:12][CH2:11][C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)(=[O:44])=[O:43])[CH:35]=3)=[O:30])=[CH:46][CH:47]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)Cl)ccc2c1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(S(=O)(=O)NCc3cccc4ccccc34)ccc2c1O
Reaction time: 18 h

Procedure:
To a stirred solution of 44 μL of 1-naphthylmethylamine and 51 μL of diisopropylethylamine in 0.5 mL of pyridine is added 100 mg of 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-7-quinolinesulfonyl chloride from Preparation No. 31. After 18 h, the solution is added to 3.5 mL of rapidly stirred 2 N HCl, and the resulting solid is filtered, washed well with water, and dried under vacuum. Flash chromatography of the solid on silica gel using 2-5% methanol in dichloromethane provides 48 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:2]3[C:11]4[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=4[O:12][CH3:13])[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc12
Yield: 91.9 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-quinolin-3-carbonitrile, 0.093 g of 6-aminoindazole, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.189 g of 4-(1H-indazol-6-ylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 302-305° C.; mass spectrum (EI, m/e): M 345.1223.
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]CC2C=CC=CC=2)[CH:6]=1)=[O:4].CC1CC=CCC=1>CCO.[Pd]>[OH:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH:2]([CH3:1])[CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(CCN1CCOCC1)C(=O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CC(CCN1CCOCC1)C(=O)c1cccc(O)c1
Yield: 98.3 %

Procedure:
To a solution of the product of Step 1 (119 mg, 0.34 mmol) in EtOH (10 mL), was added 10% palladium on carbon (50 mg), followed with 1-methyl-1,4-cyclohexadiene (1 mL). This suspension was then heated to reflux for 15 min. The reaction mixture was filtered and concentrate to afford the title compound as a white solid (88 mg, 99%). MS (ES+) m/e 264 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[CH:22]=[C:21]3[C:28]#[N:29])[C:15]([CH2:30][CH3:31])=[C:14]([O:32]CC2C=CC=CC=2)[C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:28]([C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([C:16]3[NH:17][C:9](=[O:8])[C:10]([C:11]([OH:13])=[O:12])=[C:14]([OH:32])[C:15]=3[CH2:30][CH3:31])[CH:19]=2)[N:23]([CH3:27])[CH:22]=1)#[N:29]
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)[nH]c(=O)c(C(=O)O)c1O
Yield: 71.6 %

Procedure:
To a solution of 2,4-bis(benzyloxy)-6-(3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinic acid (123 mg, 0.24 mmol) in EtOAc (4 mL) was added Pd/C (10% Degussa type, 30 mg) at room temperature. The flask was evacuated then back-filled with H2 (1 atm) over three cycles. The reaction was monitored by LC-MS. Upon completion, the reaction mixture was filtered through celite then washed with MeOH (ca. 25 mL) thoroughly. The filtrated was concentrated to afford the title compound (58 mg, 72%).
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.CO>[CH:1]1([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1CCc2ccc3ccccc3c21
Reaction time: 6 h

Procedure:
A 12.36 g portion of benzindanone (63 mmole) was dissolved in 300 ml of THF and 150 ml of methanol, and 3.6 g (95 mmole) of sodium borohydride was added at room temperature. After stirring the mixture for 6 hours, the reaction was terminated with dilute hydrochloric acid, and extracted with hexane (100 ml X 2) and ether (100 ml×2). Two stereoisomers of benzindanol were obtained. The crude product was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccn2)c2ccccc2O1
Yield: 72.3 %

Procedure:
6.95 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 100 ml of ethanol and shaken at room temperature with 10% palladium-on-charcoal under a hydrogen atmosphere. After the required volume of hydrogen had been taken up the catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from n-hexane to give 5.07 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 99-101° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]2[C:16](F)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[C:10]=2[S:11][CH:12]=1.[NH2:20][C@@H:21]([C:25]([OH:27])=[O:26])[C@H:22]([CH3:24])[OH:23]>CS(C)=O>[Cl:7][C:8]1[C:9]2[C:16]([NH:20][C@H:21]([C@@H:22]([OH:23])[CH3:24])[C:25]([OH:27])=[O:26])=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[C:10]=2[S:11][CH:12]=1
Reactant: N#Cc1ccc(F)c2c(Cl)csc12
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)O
Temperature: 80 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
K2CO3 (850 mg, 6.15 mmol) was added to a mixture of 3-chloro-4-fluorobenzo[b]thiophene-7-carbonitrile (0.52 g, 2.46 mmol) and D-threonine (322 mg, 2.70 mmol) in DMSO (10 mL) at room temperature. The mixture was heated to 80° C. and stirred for 16 h. After cooling to room temperature, the reaction mixture was poured into ice-water (100 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave the crude (2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (0.73 g, 96%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.67 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 4.57 (m, 1H), 4.35 (dd, J=2.4, 8.4 Hz, 1H), 1.37 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>C(Cl)Cl>[Br:52][CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:15]1[CH:25]=[CH:26][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:31])([F:30])[F:1])=[CH:13][C:14]=1[CH2:27][CH2:28][CH3:29]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CBr)c1
Yield: 84.1 %

Procedure:
A solution of (3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)phenyl) methanol (1.09 g, 2.40 mmol) in methylene chloride (24 mL) was added with triphenylphosphine (0.95 g) and carbon tetrabromide (1.27 g) at 0° C. After completion of the reaction, the reaction solution was concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.04 g, yield 85%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].CN1CCOCC1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(OC(C)C)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([C:6]([F:7])([F:8])[F:9])[C:10]([F:11])([F:12])[F:13])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CN1CCOCC1
Product: O=S(=O)(N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 82.7 %

Procedure:
To a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (5 g, 20.2 mmol) in isopropyl acetate (50 mL) was added 4-methyl morpholine (5 mL, 45.5 mmol). The mixture was stirred at 20 to 25° C. for 5 to 10 minutes and then 4-chlorobenzenesulfonyl chloride (4.5 g, 21.3 mmol) was added. The reaction mixture was stirred at 20 to 25° C. for 6 to 18 hours. Water (25 mL) was added to the reaction mixture and the solid dissolved. The two layers were separated, the organic layer was washed with 10% NaHCO3 (25 mL) and 10% NaCl (25 mL), and heptane (50 mL) was added to the isopropyl acetate layer (about 50 mL). The mixture was reduced in volume by about half by distillation at atmospheric conditions. While the solution remained at 80 to 90° C., heptane (50 mL) was added over 5 to 10 minutes. A solid began to form during heptane addition. After addition, the mixture was cooled to 20 to 25° C., the solution was stirred for 1 to 2 hours, and then further cooled to 5 to 10° C. for 1 hours. The solid was collected by filtration, washed with heptane (15 mL), and oven-dried to give 6.44 g (83%) of an off-white solid. 98% area HPLC purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[C:8]1[N:9](O)[C:10]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]3[N:21]=[CH:22][CH:23]=[CH:24][C:12]=3[C:11]=2[N:25]=1.P(OC(C)C)(OC(C)C)OC(C)C>CN(C)C(=O)C.C(#N)C.O>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[NH:9][C:10]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]3[N:21]=[CH:22][CH:23]=[CH:24][C:12]=3[C:11]=2[N:25]=1
Reactant: On1c(-c2c(Cl)cncc2Cl)nc2c1-c1cnccc1Nc1ncccc1-2
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC#N
Product: Clc1cncc(Cl)c1-c1nc2c([nH]1)-c1cnccc1Nc1ncccc1-2
Temperature: 25 °C

Procedure:
The crude product from above, 2-(3,5-dichloropyridin-4-yl)imidazo[4,5-d]dipyrido[2,3-b:3′,4′-f]azepin-3(8H)-ol, (0.416 mmol, Intermediate D-8) was dissolved in N,N-dimethylacetamide (1.50 mL) and triisopropyl phosphite (0.19 mL, 0.83 mmol) and heated to 160° C. for 1 h. The mixture was cooled to room temperature, then diluted with acetonitrile and water and the product isolated by preparative HPLC. The pure fractions were combined, concentrated, and then lyophilized to provide the desired product as a yellow powder. 1H NMR (DMSO-d6, 2 tautomers) δ 13.01 (bs, 1H), 8.84 (s, 2H), 8.65 and 8.52 (bs, 1H), 8.42 and 8.15 (bs, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.75 and 7.44 (d, 1H), 6.81 (m, 2H). LC/MS: 381, 383 (M+H)+.
Reaction SMILES: [C:1]([P:4](=[O:9])([O:7]C)[O:5][CH3:6])(=[O:3])[CH3:2].[I-].[Na+:11]>CC(C)=O>[C:1]([P:4](=[O:7])([O-:9])[O:5][CH3:6])(=[O:3])[CH3:2].[Na+:11]
Reactant: COP(=O)(OC)C(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COP(=O)([O-])C(C)=O

Procedure:
Dimethyl acetylphosphonate (10 g, 0.066 mol) and sodium iodide (15 g, 0.1 mol) were dissolved in acetone (80 ml) and the solution was stirred and refluxed for 6 hours. After cooling, the precipitated solid was filtered off, washed with acetone and ether and then air dried. Yield=9.5 g, m.p. decomp >170°. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 87 mg of 4-fluoro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.90 (t, 1H, J=8.8 Hz, 4.4 Hz), 7.17 (t, 1H, J=7.6 Hz), 7.38-7.46 (m, 5H), 7.52 (d, 2H, J=8 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.70 (d, 1H, J=8.8 Hz), 7.83 (td, 1H, J=8.4, 1.8 Hz), 10.09 (s, 1H). MS: m/z 390.9 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[CH3:40][N:41](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:41][CH3:40])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][C:34]([F:35])([F:36])[F:37])[CH:30]=[CH:29][C:27]=2[N:28]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCNC(=O)OC(C)(C)C
Yield: 50.8 %

Procedure:
{2-[5-Methylcarbamoyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-benzoimidazol-1-yl]-ethyl}-carbamic acid tert-butyl ester (39.0 mg) was prepared by following General Procedure F starting from 1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (80.0 mg) and DIEA (0.05 mL) in DMF (1.0 mL).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2)[CH3:2].[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[Na+]>OS(O)(=O)=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2)[CH3:2]
Reactant: CCc1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CCc1cc2c(cc1[N+](=O)[O-])NCC2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 17 mmol) in H2SO4 (98%, 20 mL) was slowly added KNO3 (1.7 g, 17 mmol) at 0° C. After addition, the mixture was stirred at 0-10° C. for 10 min, carefully poured into ice, basified with NaOH solution to pH 9 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 58%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[C:33]([CH2:35][C:36]([NH:38][CH2:39][CH3:40])=[O:37])#[N:34].N1CCCCC1>CO>[C:33]([C:35](=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([NH:14][C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:32])([CH3:1])[CH3:31])=[CH:6][N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:8]3=[N:9][CH:10]=2)=[CH:16][CH:17]=1)[C:36]([NH:38][CH2:39][CH3:40])=[O:37])#[N:34]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CCNC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (30 mg, 0.070 mmol) was dissolved in methanol (5 ml) and 2-cyano-N-ethyl-acetamide (11.38 mg, 0.1000 mmol) and piperdine (0.01 ml, 0.1300 mmol) were added. The reaction mixture was stirred at room temperature for 5 hr. The solvent was evaporated, the residue was loaded on a silica gel column and eluted with CH2Cl2 to MeOH 0-2, 3% to yield 37 mg of 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide.