Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O>C(#N)CC>[Cl:15][CH2:16][C:17]1[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][CH:8]=2)[S:14][CH:19]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Solvent: CCC#N
Product: ClCCCOc1ccc(-c2nc(CCl)cs2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
4-(3-chloropropoxy)benzenecarbothioamide ax71 (0.9 g, 4 mmole, 1 eq) is dissolved in propionitrile (20 ml) and 1,3-dichloroacetone (0.6 g, 4.7 mmole, 1.17 eq) is added. The mixture is refluxed 1 h at 100° C. then concentrated to dryness. The crude material is taken up in dichloromethane, washed with water and dried over magnesium sulfate. The residue is triturated in diisopropylether and filtered off to give 1.1 g of 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole ax72 as a white solid.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25](O)[CH3:26])=[N:23][CH:24]=1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.C(OCC)C>[N:15]([CH:25]([C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=1)[CH3:26])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccc(Cl)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Cl)cn1
Reaction time: 3 h

Procedure:
Diphenylphosphoryl azide (1.0 mL) was added to a solution of 1-(5-chloropyridin-2-yl)ethanol (503 mg) in toluene (8 mL) in a nitrogen atmosphere. The reaction solution was ice-cooled, and 1,8-diazabicyclo[5,4,0]undec-7-ene (0.69 mL) was added dropwise to the solution. The reaction solution was stirred for three hours. Then, the solution was returned to room temperature and stirred overnight. Water and diethyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-diethyl ether) to obtain 337 mg of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1(O)[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:6]1[C:7](OC)=[O:8].O.Cl>CO.C[O-].[Na+]>[OH:3][NH:2][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:5]=1[OH:4]
Reactant: COC(=O)C1C=CC(C)=CC1(O)O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NO)c(O)c1
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
9.05 g of hydroxylamine hydrochloride was dissolved in 84 mL of methanol, to which 40.64 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this mixture was stirred for 10 minutes. Then, 21 mL of a solution of 7.00 g of methyl 2-hydroxy-4-methylsalicylate in methanol was added dropwise to the reaction mixture, which was stirred for one hour at room temperature and then another four hours while heating it under reflux. The reaction mixture was added to water, and adjusted to pH 5 with 6M hydrochloric acid, and then resultant precipitate was filtered out thereof. The resultant solid was washed with water and diisopropyl ether successively to yield 5.95 g of N,2-dihydroxy-4-methylbenzamide as light yellow solid.
Reaction SMILES: Br.[NH:2]=[C:3]1[N:7]([CH2:8][C:9](O)=O)[CH:6]=[CH:5][S:4]1.P(Br)(Br)([Br:14])=O.[OH-].[Na+]>>[Br:14][C:9]1[N:2]=[C:3]2[N:7]([CH:8]=1)[CH:6]=[CH:5][S:4]2
Reactant: N=c1sccn1CC(=O)O
Reactant: O=P(Br)(Br)Br
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Brc1cn2ccsc2n1
Temperature: 140 °C

Procedure:
A mixture of 10.0 g of 2-imino-4-thiazolin-3-yl-acetic acid hydrobromide and 30.0 g of phosphorus oxybromide is heated for 2 hours at 140° C. After cooling, the reaction mixture is poured into ice water, neutralized with 10% sodium hydroxide solution and filtered to collect the precipitated crystals. The crystals are recrystallized from toluene to afford the title compound of mp. 96°-98° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[CH:12][CH:11]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2[nH]c(-c3ccccn3)cc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (49.0 mg, yield 23%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:13]
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C
Yield: 3.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-toluidine (1.25 g, 11.7 mmol) in 10 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol and recrystallized from acetonitrile-DMF to yield 0.11 g of the title compound, mp 224°-225° C (dec.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][NH:28][CH3:29]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:28]([CH3:29])[CH3:27])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CC3CC3)n2)cc1F
Yield: 88.1 %

Procedure:
Following the procedure of Example 7, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 88.1%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCCCCCC(=O)O
Product: CCCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and heptanoic acid
Reaction SMILES: Cl[CH2:2][CH:3]([OH:9])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+:10].[NH4+:11]>>[NH2:11][CH2:2][CH:3]([OH:9])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[Na+:10]
Reactant: [NH4+]
Reactant: O=S(=O)([O-])CC(O)CCl
Agent: [Na+]
Product: NCC(O)CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 3-chloro-2-hydroxypropanesulfonate (1.97 g, 10 mmol) was dissolved in 12.5% aq. ammonium solution and it was stirred at room temperature overnight. Ammonia was removed by concentrating the solution in evaporator and Sodium 3-amino-2-hydroxypropanesulfonate was obtained. Sodium 3-amino-2-hydroxypropanesulfonate (177 mg, 1 mmol) was dissolved in water (10 ml), NaHCO3 (84 mg, 1 mmol) and lauroyl chloride (231 μl, 1 mmol) were added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the compound was absorbed by adding Wakogel 50C18 (2 cm3), the gel was loaded into a column and washed with water (50 ml), and eluted with methanol (10 ml). The elution was cooled to give PHL (sodium 2-hydroxy-3-lauramide-1-propansulfonate) as a crystalline. MALDI-TOF-MS [M+Na]+ m/z=381.75.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]3[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]3=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1ncc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reactant: OB(O)c1cncc(F)c1
Product: CC(C)n1ncc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(6-chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)phenol (b) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Product: Cc1ccc2nc(C)oc(=O)c2c1

Procedure:
45.5 g (0.3 mol) of 5-Methylanthranilic acid are refluxed together with 130 g of acetic anhydride for 3 hours. After the solvent has been evaporated in vacuo, the residue is dissolved in 200 ml of dichloromethane, and the solution is filtered through silica gel. The concentrated filtrate is induced to crystallise with isopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH2:38]([NH:41][C:42]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH2:45])=[O:43])[CH2:39][CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:45][N:44]([CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:42]([NH:41][CH2:38][CH2:39][CH3:40])=[O:43])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CCCNC(=O)N(N)Cc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)N(Cc1ccccc1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (1.50 g, 5.04 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (524 μL, 6.01 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (30.1 μL, 0.41 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then concentrated to remove residual oxalyl chloride and the resulting oil was redissolved in ethyl acetate (10 mL). This solution was then added dropwise to a suspension of N-propyl-1-phenylmethylhydrazine carboxamide methanesulfonate (1.52 g, 5.01 mmol) and pyridine (970 μL, 12.6 mmol) in ethyl acetate (15 mL) at 0° C. After stirring at 0° C. for 1 h, the solution was warmed to rt and washed with 1N HCl (2×20 mL) and 5% aq. NaHCO3 (2×20 mL) followed by sat'd aq. NaCl (20 mL). The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, 1:1 ethyl acetate:hexanes) to afford the title compound as a clear oil (1.42 g, 59%): 1H NMR (DMSO-d6, 60° C.) δ 9.51 (s, 1H), 7.20 (m, 5H), 7.01 (d, 2H, J=8 Hz), 6.71 (t, 1H, J=7 Hz), 4.55 (s, 2H), 4.17 (q, J=7 Hz), 3.00 (q, 2H, J=7 Hz ), 2.45 (t, 2H, J=2Hz ), 2.07 (t, 2H, J=2 Hz), 1.73 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.40 (q, 2H, J=7 Hz ), 1.17 (t, 3H, J=7 Hz), 0.81 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174. 0, 172.0, 158.2, 153.8, 139.0, 135.8, 129.7, 128.84, 128.79, 127.6, 119.4, 79.2, 61.6, 51.3, 42.3, 34.3, 33.4, 27.1, 25.7, 23.7, 14.6, 11.9 ; IR (CHCl3) 3009, 1726, 1672, 1143 cm−1; Anal. Calcd. For C27H37N3O5: C, 67.05; H, 7.71; N, 8.69. Found: C, 66.65.; H, 7.63; N, 8.57.
Reaction SMILES: C(OCC1C(C2N=C(NC3C=CC(C4CCNCC4)=CC=3)C(=O)N(C)C=2)=CC=CC=1N1C(=O)C2SC3CCCCC=3C=2CC1)(=O)C.[C:47]([O:50][CH2:51][C:52]1[C:57]([N:58]2[CH2:69][CH2:68][N:67]3[C:60](=[CH:61][C:62]4[CH2:63][C:64]([CH3:71])([CH3:70])[CH2:65][C:66]=43)[C:59]2=[O:72])=[CH:56][C:55]([F:73])=[CH:54][C:53]=1B1OC(C)(C)C(C)(C)O1)(=[O:49])[CH3:48].Br[C:84]1[CH:85]=[C:86]([NH:92][C:93]2[CH:98]=[CH:97][C:96]([CH:99]3[CH2:103][CH2:102][CH2:101][N:100]3[CH3:104])=[CH:95][N:94]=2)[C:87](=[O:91])[N:88]([CH3:90])[CH:89]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.CO.COCCOC>[F:73][C:55]1[CH:54]=[C:53]([C:84]2[CH:85]=[C:86]([NH:92][C:93]3[CH:98]=[CH:97][C:96]([CH:99]4[CH2:103][CH2:102][CH2:101][N:100]4[CH3:104])=[CH:95][N:94]=3)[C:87](=[O:91])[N:88]([CH3:90])[CH:89]=2)[C:52]([CH2:51][O:50][C:47](=[O:49])[CH3:48])=[C:57]([N:58]2[CH2:69][CH2:68][N:67]3[C:60](=[CH:61][C:62]4[CH2:63][C:64]([CH3:70])([CH3:71])[CH2:65][C:66]=43)[C:59]2=[O:72])[CH:56]=1
Reactant: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCNCC4)cc3)n2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCCN4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 67 %

Procedure:
Example 243a was synthesized using the same procedure as 121b, except using compound 230a (446 mg, 0.9 mmol), 5-bromo-1-methyl-3-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)pyridin-2(1H)-one (229a) (281 mg, 0.8 mmol), 1M sodium carbonate solution (2.7 mL, 2.7 mmol), tetrakis(triphenylphosphine)-palladium(0) (47 mg, 0.040 mmol) and 1,2-dimethoxyethane (6.5 mL).The reaction mixture was heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromato-graphy (silica, 9:1 methylene chloride/methanol) give a 67% yield (350 mg) of 243a as brown oil: MS (ESI+) m/z 653.1 (M+H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C)C=O.[OH-].[K+].[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1S(C)(=O)=O>O>[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[S:3][CH2:1][CH3:2]
Reactant: CCS
Reactant: Cn1cc([N+](=O)[O-])nc1S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc([N+](=O)[O-])cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Ethyl mercaptan (5.14 g, 0.083 mole) was added to dimethylformamide (140 ml) containing potassium hydroxide (4.6 g, 0.08 mole). This was stirred for 90 minutes until all the potassium hydroxide had dissolved. To this solution was added 1-methyl-2-methylsulfonyl-4-nitroimidazole (8.5 g, 0.04 mole) and the reaction stirred for 2 hours at room temperature. The reaction mixture was then added to water (500 ml) and stirred in an ice bath for an additional hour. The crystalline product was filtered off and dried to give 5.6 g of crude product. This was recrystallized from ethanol/water to give 4.3 g of product.
Reaction SMILES: [N+:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2=[N:8][C:9](=O)[N:10]=[C:6]2[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[N+:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2[N:8]=[C:9]([Cl:19])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1N=c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2=N1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Yield: 64.7 %

Procedure:
As represented in the following synthesis scheme, 10 g of 2-benzoimidazolone was heated and stirred in 100 mL of nitric acid (1.38) at 70° C. for 1 hour, followed by diluting with cold water, to thereby obtain yellow green 5,6-dinitro-2-benzoimidazolone (yield 76.5%). The thus obtained 5,6-dinitro-2-benzoimidazolone was refluxed in phosphorous oxychloride at 140° C. for 7 hours, followed by evaporating the excessive phosphorous oxychloride under reduced pressure, and neutralizing with an aqueous solution of sodium hydrogen carbonate, to thereby obtain yellow 5,6-dinitro-2-chlorobenzimidazole the 2-position of which was chloridized (yield 64.7%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:8]([CH2:7][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10][S:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](OCC)[N:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:13][CH2:12][CH2:11][NH2:14])[N:7]=1
Reactant: CCOc1cnnc(N)n1
Reactant: NCCN
Solvent: Cc1ccccc1C
Product: NCCNc1cnnc(N)n1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
To a slurry of 3-amino-5-ethoxy-1,2,4-triazine (1.40 g, 0.0100 mol) in xylene (5 ml) was added ethylenediamine (1.00 ml, 0.0150 mol). The mixture was stirred at 120° C. for 3.5 hours, cooled, and concentrated to dryness in vacuo. The residue was stirred under ether, filtered off, and dried to give the title product, 16, (1.47 g, 95%, m.p. 186°-191° C.). TLC (20% methanol/chloroform/ammonia, silica): Rf =0.14.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:12])[C:10]=2[N:11]=1.B([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:19]([OH:21])=[O:20])(O)O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[NH2:12][C:9]1[C:10]2[N:11]=[C:2]([C:16]3[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=3)[C:19]([OH:21])=[O:20])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=C(O)c1cc(F)cc(B(O)O)c1
Reactant: Nc1ncnc2ccc(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Temperature: 80 °C

Procedure:
6-chloropyrido[3,2-d]pyrimidin-4-amine (500 mg, 2.8 mmol) 3-A in acetonitrile (5 mL) was treated with 3-borono-5-fluoro-benzoic acid (CAS 269404-73-6) (560 mg, 3 mL), PDCL2(DPPF) (202 mg, 0.28 mmol) and 1 M potassium carbonate solution (8 mL). The reaction vial was purged with nitrogen, and heated to 80° C. for 1 hour. LCMS showed 100% conversion to desired product. Yellow precipitate was collected and LCMS indicated it is pure product 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluorobenzoic acid 3. The filtrate was concentrate and purified by prep HPLC. LC/MS (ESI+): m/z 285 (M+H).
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.Cl.ClC1C=CC(OCC([C@@H]2CCCN2C(=O)[C@@H]2CCCN2)O)=CC=1.C([O:46][C:47]([N:49]1[CH2:71][CH2:70][CH2:69][C@H:50]1[C:51]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[CH:58]([OH:68])[CH2:59][O:60][C:61]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=1)=[O:52])=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1.C(Cl)Cl.C(N(CC)CC)C>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:47]([N:49]2[CH2:71][CH2:70][CH2:69][C@H:50]2[C:51]([N:53]2[CH2:57][CH2:56][CH2:55][C@H:54]2[CH:58]([OH:68])[CH2:59][O:60][C:61]2[CH:62]=[CH:63][C:64]([Cl:67])=[CH:65][CH:66]=2)=[O:52])=[O:46])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([C@@H]1CCCN1)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of trichloromethyl chloroformate (0.35 ml) THF (40 ml) was dropwise added a solution of 4-chlorobenzylamine (0.71 ml) and triethylamine (0.81 ml) in THF (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A suspension of (2S)-2-[2-(4-chlorophenoxy)-1-hydroxyethyl]-1-(L-prolyl)pyrrolidine hydrochloride which had been obtained by treating (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-[2-(4-chlorophenoxy)-l-hydroxyethyl]pyrrolidine (2.13 g) with 4N hydrochloric acid in 1,4-dioxane (20 ml), and triethylamine (0.81 ml) in methylene chloride (20 ml) was dropwise added to the reaction mixture, followed by stirring at room temperature for 1 hour. 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 2.09 g of the title compound.