Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Product: CCOC(=O)C[C@H]1C[C@@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and ethyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:12][C@@H:13]1[CH:17]([O:18][CH3:19])[O:16][C@H:15]([CH2:20][OH:21])[C@H:14]1[OH:22].CO>CN(C)C=O>[F:12][C@H:13]1[C@H:14]([O:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH3:3])=[CH:5][CH:6]=2)[C@@H:15]([CH2:20][O:21][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([CH3:8])=[CH:6][CH:5]=2)[O:16][CH:17]1[O:18][CH3:19]
Reactant: Cc1ccc(CBr)cc1
Reactant: COC1O[C@H](CO)[C@@H](O)[C@@H]1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC1O[C@H](COCc2ccc(C)cc2)[C@@H](OCc2ccc(C)cc2)[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
In a nitrogen atmosphere, 0.44 g of sodium hydride and 2.03 g of 4-methylbenzyl bromide were added to a solution of 0.70 g of (2R,3R,4S)-4-fluoro-2-(hydroxymethyl)-5-methoxyoxolan-3-ol in 7.0 mL of N,N-dimethylformamide under cooling on ice, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 2.5 mL of methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate and hexane were then added thereto. The reaction mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 60/40), so as to obtain 1.33 g of (3S,4R,5R)-3-fluoro-2-methoxy-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)oxolane in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30](Cl)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:30]([O:29][CH3:28])=[O:31])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: COC(=O)Cl
Product: COC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 52 %

Procedure:
According to the procedure for compound 398 using methylchloroformate (20 mg, 0.21 mmol) afforded 13.6 mg (52% yield) of 476, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])(=[O:3])[NH2:2].[C:30]([SH:33])(=[O:32])[CH3:31].[H-].[Na+].O>CN(C)C=O>[C:30]([S:33][C@@H:10]1[CH2:9][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:7]([CH2:6][O:5][CH2:4][C:1](=[O:3])[NH2:2])[CH2:11]1)(=[O:32])[CH3:31]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-2-(carbamoylmethyl)oxymethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.98 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.25 ml) and sodium hydride (62.8% in oil suspension) (0.11 g) in dimethylformamide (10 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 3 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×3), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 v/v) to give (2S,4S)-4-acetylthio-2-(carbamoylmethyl)oxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.72 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[Na].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)=O>O1CCCC1>[C:12]1([CH2:11][O:18][C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: O=C=O
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1

Procedure:
To a solution of 6-aminocaproic acid (15 g, 0.114 mole) in a 5% aqueous solution of sodium hydroge carbonate (500 ml) and tetrahydrofuran (100 ml), was added benzylchloroformate (19.52 ml, 0.137 mole) dropwise over a 10 minute period. The reaction was allowed to stir at room temperature until carbon dioxide had ceased to eliminate (~24 hours). The reaction was concentrated in vacuo to remove tetrahydrofuran and the aqueous layer was extracted with ethyl acetate and concentrated again to remove organic residue and then acidified to pH 3 and extracted with ethyl acetate (4×), dried over anhydrous magnesium sulfate and concentrated to yield a clear oil. The product was crystallized from ethyl acetate:hexane (1:1). The white solid was recrystallized twice to yield 22.5 g of the title A compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15]1([C:20](O)=O)[CH2:19][CH2:18][CH2:17][CH:16]=1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:15]4[CH2:19][CH2:18][CH2:17][CH:16]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(O)C1=CCCC1
Product: CC1(C)C(=O)Nc2cc3[nH]c(C4=CCCC4)nc3cc21

Procedure:
Analogously to Example 11, a mixture of 0.48 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.31 g. (1-cyclopenten-1-yl)-carboxylic acid is well stirred up with 4.5 g. warm polyphosphoric acid and then stirred for 30 minutes in a bath with a temperature of 200° C. After cooling, the reaction mixture is triturated with ice water, adjusted to pH 7-8 with concentrated aqueous ammonia solution and insoluble material is filtered off with suction, washed with water and dried, 0.51 g. of crude product thereby being obtained. This is repeatedly triturated with 6 ml. amounts of methanol, 0.25 g. of substance thereby remaining undissolved. This product is triturated three times with 6 ml. amounts of a mixture of methylene chloride/methanol (1:1 v/v), 0.14 g. of the desired title compound thereby being obtained which, per mole, still contains 2/3 mole methanol and 1 mole water; m.p. 233°-235° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](Cl)=[O:7])[CH:2]=[CH2:3].[C:9]([O:12][CH2:13][CH:14]([NH:20][C:21]([C:23]1[C:28]([I:29])=[C:27]([NH2:30])[C:26]([I:31])=[C:25]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:24]=1[I:46])=[O:22])[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>CN(C)C(=O)C>[C:43]([O:42][CH2:41][CH:35]([NH:34][C:32]([C:25]1[C:26]([I:31])=[C:27]([NH:30][C:6](=[O:7])[CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[C:28]([I:29])=[C:23]([C:21]([NH:20][CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][O:12][C:9](=[O:11])[CH3:10])=[O:22])[C:24]=1[I:46])=[O:33])[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:45])[CH3:44]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: C=CCOCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCOCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Temperature: 5 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
Allyloxyacetyl chloride (9.0 g, 67 mmol) was added dropwise to a stirred solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5 -amino-2,4,6-triiodo-1,3-benzenedicarboxamide (30.0 g, 34 mmol) in N,N-dimethylacetamide (70 ml) at 0°-5° C. The reaction mixture was stirred at 5° C for 30 minutes and at room temperature for 20 hours. It was then slowly added dropwise to a well stirred mixture of ice-water (1.5 L), when a white solid separated out. This was collected by filtration, washed with water, and dried in vacuo to obtain N,N'-Bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2-propenyloxy)acetyl]amino-2,4,6-triiodo-1,3-benzenedicarboxamide as a white amorphous solid (32.1 g, 97% yield), m.p. 214°-16°.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 53a (0.4 g, 0.8 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.5 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]([NH2:28])[CH3:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:29](O)(=[O:33])[C:30]#[C:31][CH3:32]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]([NH:28][C:29](=[O:33])[C:30]#[C:31][CH3:32])[CH3:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: C[C@H](N)c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Product: CC#CC(=O)N[C@@H](C)c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 26.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(1-aminoethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 45) and 2-butynoic acid, to afford the title compound (9.5 mg, 26.9%). Data: UPLC(C) Rt: 1.38 min; m/z 440.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]Br.[OH-].[Na+]>O>[Br:9][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[Cl:8]
Reactant: BrBr
Reactant: Clc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Br)c(Cl)c1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In a 1,000 ml four necked flask equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, 588 g (4 mole) of metadichlorobenzene and 8 g of ferric chloride were charged, and 640 g (4 mole) of bromine was added dropwise to the mixture at room temperature with stirring. The reaction was carried out for about 3 hours. After the reaction, the reaction mixture was poured into water and it was neutralized with sodium hydroxide. The reaction product was extracted with chloroform. The extract was washed with water and dried and was distilled under a reduced pressure to obtain 890 g of 1-bromo-2,4-dichlorobenzene (yield: 98.5%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH2:5]([C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:27])[CH2:11][CH:10]=1)[CH3:6]>CO.ClCCl>[CH2:5]([C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH:10]=1)[CH3:6]
Reactant: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
ix)—A solution of sodium borohydride (0.21 g) and sodium hydroxide (0.44 g) in methanol (50 ml) was added dropwise to a solution of (7α)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (4.31 g) in dichloromethane (12 ml) and methanol (20 ml), cooled to 0° C. The reaction mixture was stirred for 1.5 h, quenched with acetone (4 ml), and then poured into a saturated aqueous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,17β)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (4.28 g). The product was used in the following step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NCc1cccnc1
Reactant: O=C1CCCCCCCCCCCCCC1
Product: c1cncc(CNC2CCCCCCCCCCCCCC2)c1

Procedure:
Following the general procedure of Example 33, but starting with 3-aminomethylpyridine and cylcopentadecanone, the title compound is produced, NMR (CDCl3, TMS) δ 8.58, 7.72, 7.25, 3.76, 2.56, 1.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C@H:7]2[NH:14]C(=O)OC(C)(C)C.CO.Cl>O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C@H:7]2[NH2:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2c1ccc(F)c2Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1(C)C[C@@H](N)c2ccc(F)c(Cl)c2O1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
The crude (R)-tert-butyl 8-chloro-7-fluoro-2,2-dimethylchroman-4-ylcarbamate (4.47 g, 13.5 mmol), MeOH (36 mL), and concentrated HCl (4 mL) were heated to 50° C. After 2 h, complete deprotection observed by LCMS. The reaction mixture was cooled, stirred for 8 h, then diluted with methyl tert-buthy ether (60 mL) and water (40 mL). The mixture was paritioned and the organic layer was extracted with water (50 mL). The aqueous layer was basified with 2N NaOH (40 mL) and extracted with dichloromethane (2×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound (2.87 g, 12.50 mmol, 92% yield). MS (ESI+) m/z 230 (M+H)+.
Reaction SMILES: [S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(O)(=[O:3])=[O:2].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CS(=O)(=O)O
Product: CCOC(=O)CS(=O)(=O)Cl
Temperature: 125 °C

Procedure:
1H NMR (CDCl3): δ1.35 (t, 3H), 4.1 (s, 2H), 4.25 (q, 2H). A mixture of ethyl sulfoacetate (16.82 g, 100 mM) and POCl3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours. The mixture was cooled and filtered, and excess POCl3 was removed to give ethyl chlorosulfonylacetate. The ethyl chlorosulfonylacetate (18.66 g, 100 mM) was added dropwise with stirring to a solution of 2,4,6-triisopropylphenol (22.1 g, 100 mM) in 50 mL CH2Cl2 maintained at 0° C. The mixture was stirred at room temperature for an additional 18 hours. The solvent was removed and the residue was redissolved in 100 mL ethyl acetate and washed with 1 N HCl and brine. The ethyl acetate was evaporated to provide ethyl (2,4,6-triisopropylphenoxysulfonyl)acetate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([OH:15])=O)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[NH2:25][CH2:26][CH:27]([OH:39])[CH2:28][N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CN(C=O)C>[CH2:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][CH2:38][N:29]1[CH2:28][CH:27]([OH:39])[CH2:26][NH:25][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=C(O)COc1cccc2cccnc12
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1cccc2cccnc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 4.2 %

Procedure:
To a stirred mixture of 2-(quinolin-8-yloxy)acetic acid (100 mg, 0.492 mmol) in DMF (5 mL) was added DIEA (95 mg, 0.738 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.492 mmol) and BOP-Cl (151 mg, 0.591 mmol). The mixture was stirred at 25° C. for 48 hours then the reaction mixture was quenched by addition of water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the desired product (8 mg, Yield: 4%). 1H NMR (400 MHz, MeOD) δ=8.91 (d, J=4.3 Hz, 1H), 8.42 (d, J=8.3 Hz, 1H), 7.69-7.54 (m, 3H), 7.30 (d, J=7.3 Hz, 1H), 7.12-6.96 (m, 4H), 4.78 (s, 2H), 4.18-4.07 (m, 1H), 3.71 (s, 2H), 3.60-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.89 (d, J=5.8 Hz, 2H), 2.84 (d, J=4.8 Hz, 2H), 2.65-2.61 (m, 2H). LCMS (m/z): 392.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([CH3:26])[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=O)[NH2:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([CH3:26])[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[S:36])[NH2:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=O)cc3)ccc2c1
Solvent: c1ccccc1
Product: COc1ccc2cc(C(C)C(=O)Oc3ccc(C(N)=S)cc3)ccc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
4-Carbamoylphenyl 2-(2-methoxynaphthalen-6-yl)-propanoate, 5 (1.80 g, 4.34 mmol) and Lawesson reagent (1.75 g, 4.34 mmol) were dissolved in 130 ml of anhydrous benzene. The reaction was warmed to 60° C. and stirred for 4 h. The solvent was removed under reduced pressure; the crude residue was purified by silica gel column (dichloromethane/methyl alcohol 9.75:0.25) to furnish 2.9 g of crude compound 6. The obtained compound was purified by a silica gel open column and eluted with CH2Cl2/MeOH (9.5/0.5)) giving the pure compound 6 (970 mg, 61% yield).
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39]>C1COCC1.CCO>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of NaH (1.87 g, 77.9 mmol) in THF (26 mL) under nitrogen was slowly added EtOH (80 mL, Aldrich>99.5%, 200 proof) and the resulting homogeneous solution was stirred for 10 minutes. The sodium ethoxide solution was then added to a mixture of 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide (37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resulting mixture was stirred at room temperature for 1 h before being concentrated in vacuo. The residue was suspended in water (500 mL) and the mixture was sonicated and stirred for about 1 h at room temperature until the remaining solid became a filterable powder. The resulting powder was collected, triturated with ethyl ether (50 mL) and dried under high vacuum for 48 h to afford 3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (30.8 g, 95%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[C:10]([NH2:18])[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1
Reactant: [H][H]
Reactant: CC1CC(=O)NN=C1c1ccc(NC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NC2CC2)c(N)c1

Procedure:
5.8 gm of 5-methyl-6-(3-nitro-4-cyclopropylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were hydrogenated in a mixture consisting of 100 ml of ethanol and of 20 ml of glacial acetic acid in the presence of 0.5 gm of 10% palladium charcoal at a hydrogen pressure of 5 bar. 120 ml of glacial acetic acid were added, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was reacted further without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(OC)c(N(CCCl)CCCl)c1
Agent: Cl
Product: COc1ccc(C(=O)O)cc1N(CCCl)CCCl
Yield: 79.5 %

Procedure:
A suspension of methyl 3-bis(2′-chloroethyl)amino-4-methoxybenzoate (2.70 g, 8.823 mmol) in concentrated HCl (37% w/w in H2O, 40 mL) was heated to reflux under N2 for 1 hour. The reaction mixture was treated with ice/H2O (200 mL), extracted with ethyl acetate (4×150 mL). The organic solution was concentrated to give a white solid (2.05 g, 80%). ESMS calcd for C12H15Cl2NO3: 291.0; Found: 292.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:14])=[CH2:13])[NH:6][C:5]2=[O:15].[Si]([CH:20]=[N+:21]=[N-:22])(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1([CH3:14])[CH2:13][CH:20]=[N:21][NH:22]1)[NH:6][C:5]2=[O:15]
Reactant: C=C(C)c1nc2ccc(Cl)cc2c(=O)[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: CC1(c2nc3ccc(Cl)cc3c(=O)[nH]2)CC=NN1

Procedure:
6-Chloro-2-isopropenyl-3H-quinazolin-4-one (1 mmoL) in THF (5 mL) was treated with TMSCHN2 (1.0 N, 3.0 mmoL) at 50° C. for 4 h. The solvent was removed and the residue was purified by silica gel column chromatography to yield the title compound as a white solid.