Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CN(C=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([CH2:27][CH2:26][CH2:25][CH2:24][OH:28])[CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Reactant: C#CCCO
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(CCCCO)ccc2c1O
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-7-iodo-3-quinolinecarboxamide from Example No. 39 (0.646 g), 3-butyn-1-ol (0.16 mL), PdCl2 (PPh3)2 (26.0 mg), and 0.93 mL DMF was heated at 90° C. for 1 hr. The reaction mixture was cooled to room temperature and partitioned between EtOAc and H2O. An orange solid precipitated from the organic layer and was filtered and collected to obtain pure product as indicated by NMR. The aqueous layer was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4 and condensed to obtain an orange-brown residue. The residue was adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC were combined, condensed, and recrystallized from EtOAc/hexanes to obtain a white solid. The two crops yielded 0.412 g (74%) of the desired product as an orange and white solid. A mixture of the acetylene from above (300 mg) and Pd/C (10%, 60.0 mg) was dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture was placed under the Parr hydrogenator and monitored with the OAMS for complete reduction of the acetylene. After 1 hr OAMS showed that complete reduction had not been achieved. The old palladium catalyst was replaced with fresh palladium catalyst (60.0 mg) and placed under the Parr hydrogenator for another hour. The reaction was completed in a total of 2 hrs and filtered over celite to remove the palladium. The filtrate was condensed to obtain a yellow solid. The crude product was adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC were condensed and recrystallized with EtOAc/hexanes to yield 186.2 mg (61%) of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(S(O[CH2:22][CH2:23][Cl:24])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[Cl:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccc(OCCCl)cc1

Procedure:
A mixture of methyl 4-hydroxybenzoate (15.2 g, 0.1 M), 2-(benzenesulphonyloxy)ethyl chloride (28.65 g, 0.12 M) and potassium carbonate (19.15 g, 0.1 M) in 4-methylpentan-2-one (170 ml) was stirred at reflux for 24 hours. After cooling, distilled water (170 ml) was added and the organic phase separated off. Evaporation to dryness gave a yellow solid which was crystallised from ethanol to give the title compound, yield (13.3 g), m.p. 56°-58°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.[F:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:18][CH2:17][CH2:16][F:15])[N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1
Reactant: FCCCBr
Reactant: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Yield: 57.9 %

Procedure:
A stirred solution of 4.7 g (0.022 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one, 4.0 g (0.028 mole) of 3-fluoropropyl bromide and 4.0 g (0.028 mole) of potassium carbonate in 60 ml of dimethylformamide was heated at 60° C. for 16 hours. The reaction mixture was poured into water and the mixture extracted with diethyl ether. The combined ether extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 3.5 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 62°-63° C. The reaction was repeated several times.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10]N2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18][N:19]([CH3:31])[CH2:20]CCOC1C=CC(N)=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:18][N:19]([CH3:31])[CH3:20])=[CH:16][CH:17]=1)=[C:2]=[S:3]
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1
Product: CN(C)CCCOc1ccc(N=C=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4 isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(3-dimethylamino-propoxy)-phenylamine. Title compound: ES-MS: 237.1 [M+H]+; single peak at tR=6.91 min (System 1).
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1.[OH2:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:34]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1
Reactant: O
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To a solution of 8.9 g (0.019 mol) of the compound of Example 4 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.34 mL (0.019 mol) of distilled water in 4.0 mL (0.029 mol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed under vacuum and the residue is recrystallized twice with 50 mL of acetonitrile. The acetonitrile is then removed in vacuo and the residue is dried under vacuum to give 2.4 g (79.5% yield) of the title compound as an off-white solid melting at 164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:11][C:10]1[N:9]=[C:7]([C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]2[C:12]=1[CH:13]=[N:14][C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[N:16]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(OC)cc3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccc(OC)cc4)n3n2)cc1
Yield: 73.8 %

Procedure:
Applying the Cyclization Procedure 1, using 4-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 65) (35 mg, 0.09 mmol), 1,2-dichloroethane (1.8 mL) and phosphorus oxychloride (0.068 mL, 0.73 mmol), to afford 5-methyl-N,7-bis[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (24 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=1>CO>[CH3:18][C:15]1[CH:14]=[C:13]2[NH:12][C:2]3[N:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=3[C:8](=[O:10])[N:17]2[N:16]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Cc1cc(N)[nH]n1
Solvent: CO
Product: Cc1ccc2c(=O)n3nc(C)cc3[nH]c2n1
Temperature: 25 °C

Procedure:
17.1 g. of 2-chloro-6-methylpyridine-3-carboxylic acid and 19.4 g. of 5-amino-3-methylpyrazole are heated together for 10 minutes at 180°-190°. The mixture is cooled to room temperature and treated with methanol. The crystalline 2,6-dimethylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and recrystallized from dimethylformamide, yield: 13.5 g. (64%); m.p. >300°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([CH2:10]O)=[CH:9][C:2]=12.P(Br)(Br)[Br:13].O.[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Br:13][CH2:10][C:8]1[S:7][C:3]2[C:2](=[N:1][CH:6]=[CH:5][N:4]=2)[CH:9]=1
Reactant: OCc1cc2nccnc2s1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: BrCc1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a suspension of thieno[3,2-b]pyrazin-6-ylmethanol 87 (408 mg, 2.455 mmol) in CH2Cl2 (8 mL) and THF (8 mL) was added phosphorus tribromide (1/166 mL, 12.27 mmol) and stirred overnight at rt. Water was added, alkalized with 2N NaOH and extracted with EtOAc. Organic layer was washed with NaHCO3 (aq) solution, brine, dried and evaporated. Purification by chromatography (CH2CL2) gave pure 6-(bromomethyl)thieno[3,2-b]pyrazine 47 (356 mg, 63%). NMR (400 MHz, CDCl3) 4.80 (s, 2H), 7.71 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H). (m/z)=229 and 231 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16]([CH3:17])=[O:26])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1
Reactant: CSc1ccc(F)cc1C(=O)Cn1cccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ccc(F)cc1C(=O)Cn1cccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.5 %

Procedure:
To a stirred cooled solution of 1-[5-Fluoro-2-(methylthio)phenyl]-2-(pyrrol-1-yl)ethanone (22c) (1.76 g, 7.06 mmol) in dichloromethane (12 ml) was added dropwise in 30 minutes a solution of m-chloroperbenzoic acid (71.5% grade, 1.70 g, 7.06 mmol) in dichloromethane (10 ml). After stirring for 45 minutes at 0° C., the mixture was treated with a 5% solution of sodium carbonate in water (41 ml) and was stirred for 15 minutes at room temperature. The organic phase was separated and water was extracted with dichloromethane (3×10 ml). The organic layers were dried and evaporated, the residue was chromatographed (10% dichloromethane in ethyl acetate) to afford 1.02 g of 23c as white crystals that darkened rapidly (64% yield). 1H NMR (CDCl3) δ8.42-8.35 (m, 1H); 7.61-7.51 (m, 2H); 6.68-6.62 (m, 2H); 6.26-6.24 (m, 2H); 5.41-5.17 (q, 2H, J=31.32, 17.87 Hz); 2.77 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11](=[O:13])[NH:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=c1[nH]nc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.5 %

Procedure:
To a solution of 3-2 (2.0 g, 10.6 mmol) in dichloroethane (106 mL) was added triphosgene (3.16 g, 10.64 mmol). The reaction mixture was stirred at room temperature for 3 days. An off-white precipitate formed, which was washed with dichloroethane (100 mL) and dried in vacuo to give 2.03 g (89%) of 3-3 as a tan solid. LC/MS: m/z (M+H)=213.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][C:33]([C:34](=[O:36])[NH2:35])=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:39][O:40][CH2:41][S:42]([C:45]1[CH:46]=[C:47]([OH:52])[C:48](=[CH:50][CH:51]=1)[OH:49])(=[O:44])=[O:43]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][CH2:41][S:42]([C:45]2[CH:51]=[CH:50][C:48]([OH:49])=[C:47]([OH:52])[CH:46]=2)(=[O:43])=[O:44])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][C:33]([C:34](=[O:36])[NH2:35])=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2ncc(C(N)=O)c2n1
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2ncc(C(N)=O)c2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazolglyoxylamido)-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was reacted with 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol according to the procedure described in Example 7. After purification of the crude product using the chromatographic procedure described in Example 7 and lyophilization of the product fractions, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-5-methylpyrazolo [1,5-a]pyrimidin-7-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:11][CH2:12]C[Si](C)(C)C)=[C:6]([Cl:18])[C:5]=1[NH2:19].COC(=O)C1C=C(N)C([SH:31])=C(Cl)C=1N.C(=S)=S.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:19])=[C:6]([Cl:18])[CH:7]2[S:11][C:12]([SH:31])=[N:10][CH:8]2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(SCC[Si](C)(C)C)c(Cl)c1N
Reactant: COC(=O)c1cc(N)c(S)c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: S=C=S
Product: COC(=O)C1=CC2N=C(S)SC2C(Cl)=C1N

Procedure:
This compound is synthesized as reported in U.S. Pat. No. 4,454,148. 2,5-Diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (step d in example H17) is used as starting material and after thiol deprotection (step f in example H17), the crude 2,5-diamino-3-chloro-4-mercapto-benzoic acid methyl ester is cyclized with CS2, NaOH in EtOH at 70° C. The crude is directly used in the next step without further purification; LC/MS: 275/277 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[NH3:32]>C1COCC1.C(O)C>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O-:16])=[O:15])[N:27]=1.[NH4+:32]
Reactant: N
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)[O-])n1
Product: [NH4+]
Yield: 69.8 %

Procedure:
2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid (5.1 g) and 28% aqueous ammonia (1.7 g) were mixed with a solvent mixture of THF/ethanol. Precipitated crystals were washed with acetone to obtain the above .drentified compound as white crystals (3.7 g). (Melting point: 135-140° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=3)=[N:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1

Procedure:
A solution of 1-(4Iodobenzenesulfonyl)-3-(4-methylthiophenyl)-1,4,5,6-tetrahydropyridazine (1.27 g, 2.69 mmol) in methanol (450 mL) was added to a solution of sodium periodate (0.61 g, 2.82 mmol) in water (6 mL) and stirred at a low heat for 16 hours. The resulting mixture was filtered, concentrated arylphosphonyl dihalide and purified by column chromatography on silica gel using ether/methylene chloride as an eluent to give the title compound as a solid: mp 191°-193° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])[CH:7]=4)[NH:11][C:10]3=[O:15])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 54.2 %

Procedure:
2-Oxo-2, 3-dihydro-1H-indole-5-sulfonic acid dimethylamide (90 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 100 mg (54%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][CH2:7][CH:8]([C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:31])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:9])=[CH:4][CH:3]=1>CS(C)=O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][CH2:7][C:8]([C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:31])[C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Solvent: CS(C)=O
Product: O=C(COc1ccc(Cl)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of (2S)-2-[2-(4-chlorophenoxy)-1-hydroxyethyl]-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (1.59 g) in DMSO (10 ml) was dropwise added a solution of sulfur trioxide-pyridine complex (2.69 g) in DMSO (10 ml), followed by 1 hour's stirring at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 0.85 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N-:9][CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[C:5]([N+:23]([O-])=O)[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1
Reactant: COc1ccc([N-]Cc2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(NCc2cc(OC)c(OC)c(OC)c2)c(N)c1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 23 %

Procedure:
[N-(4-methoxy-2-nitrophenyl)]3,4,5-trimethoxybenzylamide (17.1 mmol, 6.0 g) in absolute ether (100 ml) is added to LiAlH4 (63.4 mmol, 2.4 g) in absolute ether (40 ml), and the mixture is stirred at room temperature for 8-9 hours. While cooling with an ice bath, the suspension is quenched with water (40 ml) and is extracted with ether (3×100 ml). The combined organic layers are dried with MgSO4, filtered and evaporated. Recrystallisation from ethanol yields the title product as a red solid (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=3)[C:9]2=[O:24])=[CH:5][CH:4]=1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C:10]([CH3:27])([O:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=3)[C:9]2=[O:24])=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(CN2CCCC(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2CCCC(C)(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-methoxybenzyl)-3-(3,4,5-trifluorophenoxy)piperidin-2-one (250 mg) in THF (5 mL) was added lithiumhexamethyl disilazide (1M THF solution, 0.821 mL) at −78° C. under a nitrogen atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added a mixture of methyl iodide in THF (1 mL), and the mixture was stirred at −78° C. for 30 min under a nitrogen atmosphere, and at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (89 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11](Br)[CH:12]=[CH2:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][CH2:13][CH:12]=[CH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: C=CCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN[C@H](C)C(=O)OC(C)(C)C

Procedure:
D-Alanine t-butylester (68) is treated with one equivalent allyl bromide and one equivalent of triethylamine in toluene under reflux. The solvent is evaporated and the product is purified by flash chromatography on silica gel to give (69).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(OCCN2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCCN2CCCC2)c1

Procedure:
A solution of methyl 3-{[2-(1-pyrrolidinyl)ethyl]oxy}benzoate D37 (1.6 g) and sodium hydroxide (708 mg, 18.2 mmol) in MeOH (50 ml) and water (10 ml) was refluxed for 18 hours. The reaction was concentrated and water added and acidified to pH3 with 2M HCl solution. The reaction was concentrated and was added MeOH and was filtered, concentrated to give a brown solid of desired product D38 in 1.5 g. LCMS [MH+] 236.1@0.96 min (5 min run)