Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:23])=[C:11]([CH:22]=1)[CH2:12][C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[CH:15][CH:14]=1>>[Cl:6][C:7]1[C:22]2[C:19](=[O:21])[C:18]3[CH:17]=[N:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:2])[C:11]=2[C:10]([F:23])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cnccc1Cc1cc(Cl)ccc1F
Reactant: O=S(=O)(O)O
Product: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Temperature: 130 °C
Yield: 82 %

Procedure:
Fuming sulfuric acid (30% SO3 ; 0.31 mL) is added to 4-(5-chloro-2-fluorobenzyl)nicotinic acid of Preparative Example 12. The dark mixture is heated quickly to 130° C. for 10 min in a flask fitted with a cotton filled drying tube. After cooling to room temperature, the reaction mixture is quenched with ice (3 g) and extracted with methylene chloride (4×7 mL). The combined extracts are dried with Na2SO4 and the solvent is removed by roto-evaporation to yield 9-chloro-6-fluorobenzo[g]isoquinoline-5,10-dione as a yellow solid (0.045 g; 82% yield).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=O>C1(C)C=CC=CC=1>[C:1]1([C@H:7](/[N:9]=[CH:11]\[C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=N\[C@H](C)c1ccccc1
Reaction time: 1 h

Procedure:
To a (1S)-1-phenylethanamine (77.4 mL), was added a solution of ethyl glyoxylate in toluene (45–50%, 123 mL) at room temperature. After 1 hr, the mixture was evaporated in vacuo. The residue (120 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([OH:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].S(=O)(=O)(O)[OH:19]>>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8]([OH:10])=[O:9])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([OH:16])=[O:15])(=[O:19])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Product: NC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
100 g of 5-cyano-2,4,6-triiodoisophthalic acid is suspended in 400 ml of concentrated sulfuric acid and heated first under agitation for 30 minutes to 60° C., then for 2 hours to 95° C. The thus-produced, clear solution is then poured on 1.2 kg of ice and stirred for one hour in an ice bath. The thus-precipitated crude product is vacuum-filtered, dissolved under heating in 400 ml of ethanol, and the solution is combined with 70 ml of concentrated sodium hydroxide solution. After several hours of agitation in an ice bath, the thus-separated sodium salt is vacuum-filtered, washed with ethanol, and then dissolved in 200 ml of hot water. After treating the solution with active carbon, the filtrate is precipitated into 150 ml of semiconcentrated sulfuric acid. After several hours of stirring in an ice bath, the precipitate is vacuum-filtered, washed with a small amount of ice-cold water, and dried at 50° C., thus obtaining 84 g (=82% of theory) of 5-carbamoyl- 2,4,6-triiodoisophthalic acid, which conforms in its properties with the product of the alkaline saponification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](=[O:27])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Nc1cccc(-c2ccncc2)c1
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccncc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(pyridin-4-yl)aniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 74%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:11]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[C:13]([CH2:14][OH:15])=[CH:16][C:17]=3[F:18])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CO)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73; 0.10 g, 0.26 mmol) in MeOH (5 ml) at 0° C. was added NaBH4 (0.012 g, 0.33 mmol). The reaction was stirred for 10 minutes, and then quenched with water and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.088 g, 88%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.16-7.01 (m, 1H), 7.01 (br s, 2H), 6.06-5.41 (m, 1H), 5.19-5.02 (m, 1H), 4.52 (br s, 2H), 1.88-1.81 (m, 1H), 1.53 (d, J=6.6 Hz, 3H), 0.97-0.91 (m, 2H), 0.65 (br s, 2H). MS: Calcd.: 385. Found: [M+H]+ 386.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CF)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(CF)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
4-(Fluoromethyl)benzoic acid (6.20 g) was dissolved in 30 ml of benzene, and 0.3 ml of N,N-dimethylformamide was added and then 4.4 ml of thionyl chloride was added dropwise. The mixture was stirred for 1 hour at 40° C. and then heated to reflux for another 1 hour. The solvent was distilled off under reduced pressure to provide 6.70 g of the objective compound as pale yellow oil.
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.P(=O)(O)(O)O.[NH2:20][C@:21]1([CH2:42]O)[CH2:25][CH2:24][C@H:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:29][C:28]=3[CH:27]=2)[CH2:22]1>O>[P:2]([OH:13])([OH:9])([O:3][CH2:42][C@@:21]1([NH2:20])[CH2:25][CH2:24][C@H:23]([C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:29][C:28]=3[CH:27]=2)[CH2:22]1)=[O:1]
Reactant: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(CO)C3)ccc2C1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=P(O)(O)O
Solvent: O
Product: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(COP(=O)(O)O)C3)ccc2C1
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A mixture of phosphorus pentoxide (150 mg, 0.528 mmol) and 85% phosphoric acid (0.15 mL, 10.01 μmol) was stirred at 100° C. under nitrogen for 1 h before ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (Example 1, 6 mg, 0.018 mmol) was added. The solution was stirred at the same temperature for 3 h. Water (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 1 h. Purification using reverse phase HPLC (PHENOMENEX® Luna Axia 5μ c18 30×100 mm, 10 minute run, Solvent A: 10% MeOH: 90% H2O: 0.1% TFA, Solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration, and lyophilization gave ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate (4 mg, 9.38 μmol) as a white solid. LC/MS M+1=410. HPLC retention time=3.96 min (Condition C). 1H NMR (400 MHz, methanol-d4+CDCl3) δ 7.10-6.83 (m, 3H), 4.06-3.77 (m, 2H), 3.20-3.06 (m, 1H), 2.85-2.74 (m, 2H), 2.48 (dd, J=12.9, 6.9 Hz, 1H), 2.40-2.28 (m, 1H), 2.19-2.08 (m, 1H), 2.05-1.90 (m, 4H), 1.80-1.62 (m, 2H), 1.48-1.22 (m, 12H), 0.95-0.86 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24](O)=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([Cl:33])=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (7) (1.5 g, 3.7 mmol) was dissolved in dichloromethane (50 mL) and oxalyl chloride (700 mg, 5.5 mmol, 470 μL) and DMF (1 drop) were added and the reaction stirred at 20° C. for 2 h. There was a moderate evolution of gas for about 30 min as the reaction proceeded. The reaction was then concentrated in vacuo to give 9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (8) as a gum which was used into the next step without purification. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 20.8, 22.1, 26.4, 44.2, 51.8, 55.1, 70.7, 73.3, 100.7, 106.0, 108.6, 119.5, 123.4, 127.3, 127.7, 128.3, 131.9, 138.0, 138.2, 152.0. and 176.3.
Reaction SMILES: [C:1]([C@:3]1([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=C(OC)C=2OC)[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1N=[N+]=[N-])#[CH:2].[F:45]C(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl>[C:1]([C@:3]1([CH2:20][OH:21])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[F:45])#[CH:2]
Reactant: O=C(O)C(F)(F)F
Reactant: C#C[C@]1(COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: C#C[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F

Procedure:
A solution of 4′-C-ethynyl-5′-O-(dimethoxytrityl)-3′-fluoro-3′-deoxythymidine (12, X═F) (1 mmol) in a solution of 1% trifluoroacetic acid in methylene chloride (20 mL) is stirred at room temperature for 3 h and neutralized with ammonium hydroxide. Solvent is evaporated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (2-5% MeOH in methylene chloride) to give 4′-C-ethynyl-FLT (Ia, X═F).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[NH2:15].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C.Cl>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:21])([F:22])[F:20]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenyl chloroformate (0.86 mL) was added slowly to a stirring solution of 3-chloro-4-trifluoromethyl aniline (933 mg) in THF (10 mL) containing pyridine (1.07 mL) under an argon atmosphere. The reaction was stirred for 18 h then diluted with ethyl acetate (35 mL) and 1M HCl (20 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 then dried (MgSO4), filtered and evaporated. Trituration with 1:9 EtOAc:isohexanes (10 mL) at reflux followed by cooling to RT afforded a solid which was filtered to afford 1.15 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[C:23]([CH3:32])=[CH:24][C:25]([CH3:31])=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([CH3:31])=[CH:24][C:23]=2[CH3:32])=[CH:9][C:8]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cccnn2)cc1N)OCC
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Product: CCOC(Cn1nc(-c2cccnn2)cc1Nc1cc([N+](=O)[O-])c(C)cc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.09 g (3.93 mmol) of the compound of Example 80A and 996 mg (4.33 mmol) of 5-bromo-2,4-dimethylnitrobenzene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 1.38 g (77% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.OO.[ClH:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:17])=[CH:4][C:3]=1[N:9]=[C:10]1[NH:11][CH2:12][CH2:13][NH:14]1
Reactant: Cl
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Agent: OO
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1Cl
Temperature: 45 °C
Yield: 6.35 %

Procedure:
6.08 gm (0.029 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine were dissolved in 50 ml of concentrated hydrochloric acid, 200 mgm of ferric chloride were added to the solution, and the mixture was heated to 45° C. while vigorously stirring. 3 ml of 30% hydrogen peroxide were now slowly added dropwise, during which time the temperature of the reaction mixture rose to a maximum of 70° C. As soon as the temperature dropped to 40° C. again, the reaction had gone to completion. The reaction mixture was now admixed with ice, and the aqueous mixture was extracted with ether; the ether extracts were discarded. The aqueous phase was fractionally extracted at stepwisely increasing pH-values (alkalization with 2N NaOH), and the uniform fractions were combined, dried over magnesium sulfate and filtered. The ether was evaporated from the filtrate in vacuo, and the residue was dried, yielding 0.45 gm (6.35% of theory) of 2-(2,5-dichloro-4-methyl-phenylimino)-imidazolidine, m.p. 190°-191° C., Rf -value 0.6 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol, 5 parts concentrated ammonium hydroxide; carrier: silicagel G; detector: potassium iodoplatinate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:13])=[O:12].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:18]([CH2:17][CH2:16][CH2:15][NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])=[O:20])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc2ccccc2c1
Product: O=C(CCCNS(=O)(=O)c1ccc2ccccc2c1)N1CCN(c2ccncc2)CC1
Yield: 15 %

Procedure:
Using an analogous procedure to that described in Example 36, 4-(2-naphthalenesulphonamido)butyric acid was reacted with 1-(4-pyridyl)piperazine to give N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}naphthalene-2-sulphonamide in 15% yield as a foam;
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[C:19]#[N:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:25].Cl>CCO>[ClH:25].[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:10]3[S:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[C:11]=3[C:19]([NH2:20])=[N:21][C:4]=2[CH:3]=1
Reactant: N#Cc1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)c(F)cc2Nc2sc3ccccc3c21
Temperature: 25 °C

Procedure:
Combine 2-(4,5-difluoro-2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (2.03 g, 6.13 mmol) and Tin(II) chloride (3.49 g, 18.4 mmol) in a mixed solvent of EtOH (20 mL) and 5.0 N HCl (20 mL), heat the suspension to reflux for overnight, cool to RT. The title compound 2.05 g btaine as a yellow solid by suction filtration. 1H NMR (300 MHz, DMSO-d6): δ 11.56 (br, 1H), 10.06 (br, 1H), 9.14 (br, 2H), 7.96-7.85 (m, 1H), 7.71-7.64 (m, 1H), 7.49-7.42 (m, 1H), 7.34-7.29 (m, 1H), 7.22-7.16 (m, 1H), 7.11-7.04 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:21]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC>[C:21]([CH:25]1[CH2:26][CH2:27][CH:28]([NH:31][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:20])=[CH:13][CH:14]=2)[CH2:29][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1ccc(C(=O)N(CCC(=O)O)CC2CC2)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC(NCc2ccc(C(=O)N(CCC(=O)O)CC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above resin bound 3-[cyclopropylmethyl-(4-formylbenzoyl)amino]propionic acid (50 mg) was treated with 1 mL 0.5 M (0.5 mmol, 77.5 mg) 4-tert-butylcyclohexylamine solution in DMF:trimethylorthoformate 1:1, 100 μL glacial acetic acid and sodium cyanoborohydride (750 μmol, 48 mg) suspended in 0.5 mL DMF:trimethylorthoformate 1:1. Overnight shaking at 25° C. followed by filtration and washing with 2×1 mL 20% H2O in DMF, 3×1 mL DMF and 2×1 mL dichloromethane afforded the desired product.
Reaction SMILES: C([O:8][CH2:9][CH:10]([C@H:12]1[CH2:16][O:15][C@@H:14]([CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:13]1)[OH:11])C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[Si:19]([O:18][CH2:17][C@H:14]1[O:13][C@@H:12]([CH:10]([OH:11])[CH2:9][OH:8])[CH2:16][O:15]1)([C:32]([CH3:34])([CH3:35])[CH3:33])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1OC[C@H](C(O)COCc2ccccc2)O1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC[C@@H]1OC[C@H](C(O)CO)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of (-)-(2R,4R)-4-(2-benzoxy-1-hydroxyethyl)-2-(t-butyldiphenylsilyloxy-methyl)-dioxolane (2.52 g, 5.0 mmole) in methanol (40 ml) was added a 0.078M solution of sodium methoxide (7.3 ml) in methanol. The mixture stirred at room temperature for two hours. The mixture was neutralized with acetic acid and concentrated. The residue was then portioned between ethyl acetate and water, and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with a saturated NaHCO3 solution and then water, and then dried, evaporated, and purified by column chromatography over silica gel to yield 6 (1.9 g, 95%) as colorless oil: [α]25D-2° (C 0.25, MeOH); 1H NMR (DMSO-d6) δ1.00 (s, 9H, t-Bu), 3.40-3.52 (m, 3H, CH2OH and CHOH), 3.64 (d, J=3.7 Hx, 2H, CH2OTBDPS), 3.82-3.95 (m, 3H, 4.5-H), 4.49 (t, J-5.3 Hz, 1H, pri OH, D2O exchangeable), 4.82 (d, J=5.1 Hz, 1H, sec OH, D2O exchangeable), 5.01 (t, J-3.7 Hz, 1H, 2-H), 7.36-7.71 (m, 1OH, Ar--H); Anal. Calcd for C22H33H30O5Si: C, 65.63; H, 7.53. Found: C, 65.72; H, 7.52.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 8.7 g. (0.03 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, (Example 30) 3.06 g. (0.03 mole) of 3-dimethylaminopropylamine and 3.18 g. of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 150 ml. of water and was extracted with 150 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and the ether was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. The ethyl acetate was evaporated and the residue was dissolved in anhydrous diethyl ether and the solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was dried to give 1.9 g. of product as the hydrochloride, monohydrate, m.p. 75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]CC2C=CC=CC=2)[N:6]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[NH:6][C:7](=[O:11])[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(=O)[nH]3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 0.90 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-benzyloxypyridine, 0.1 g of 10% palladium/carbon and 5 ml of ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.60 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone. 1H-NMR(CDCl3/250 MHz) δ(ppm): 3.54 (s, 3H), 6.11 (d, 1H, J=7.9 Hz), 6.33 (s, 1H), 6.44 (d, 1H, J=7.8 Hz), 7.09 (d, 1H, J=6.7 Hz), 7.37 (d, 1H, J=8.9 Hz), 7.55 (dd, 1H, J=7.9,7.8 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH2:12][CH2:13]O)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][Cl:19])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)ccc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 4 parts of 5-chloro-2-ethyl-1H-benzimidazole-1-propanol and 150 parts of trichloromethane are added dropwise 9.6 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is taken up in water and stirred with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 5-chloro-1-(3-chloropropyl)-2-ethyl-1H-benzimidazole.