Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:51])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:51])=[O:3])[CH2:7][CH2:8]2)[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCN(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-piperidin-1-yl)-acetic acid ethyl ester (0.11 mmol) in methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating at 60° C. for 6 h cool to room temperature and dilute with water (20 mL). Extract the organics with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum, to afford the title compound as a colorless foam. MS (ES+): 708 (M+H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:15][CH3:16].[N:22]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:38]=[C:37]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:36][C:35]=3[S:43]([NH2:46])(=[O:45])=[O:44])=[CH:30][CH:29]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CO>[CH2:13]([O:17][CH2:18][C:19]([NH:46][S:43]([C:35]1[S:36][C:37]([CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:38][C:34]=1[C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:33][CH:32]=1)(=[O:44])=[O:45])=[O:21])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOCC(=O)O
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOCC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 21.4 %

Procedure:
CDI (1,1′-carbonyl-diimidazole, 129.5 mg, 0.80 mmol) was added to a solution of butoxyacetic acid (103.8 μL, 0.80 mmol) in dry THF (4 mL). The mixture was stirred at 50° C. for 2.5 h. A solution of 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (see Example 1(f) above; 100 mg) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 19.9 μL, 0.133 mmol) in dry THF (4 mL) was added to the reaction mixture. The reaction mixture was then stirred overnight at 50° C. MeOH (20 mL) was added to the reaction mixture, which was then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and then washed with water (3×50 mL). The organic phase was dried and evaporated. The crude product was purified by column chromatography using 10% MeOH in CHCl3 as eluent to give the title compound (27 mg, 0.057 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:13][C:12]=2[OH:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: COc1ccc(N=Nc2ccc(O)cc2O)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N=Nc2ccc(OCCC[Si](C)(C)C)cc2O)c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(4-methoxy-2-nitrophenylazo)benzene-1,3-diol (2.5 g, i.e. 0.0086 mol) and potassium carbonate (1.24 g) in 30 ml of dimethylformamide was brought to 70-75° C. 3-Chloropropyltrimethylsilane (1.24 g, i.e. 0.0086 mol) was added thereto over 20 minutes. The mixture was stirred at 75° C. for 6 hours. The reaction mixture was then poured into 50 ml of water and extracted with diisopropyl ether. The organic phase was dried, concentrated and purified by column chromatography (eluent: 50/50 heptane/CH2Cl2) to give compound (9) in the form of a red powder.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH3:13])[N+:19]([O-:21])=[O:20]
Reactant: CCC(Oc1ccccc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 57.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.64 g of 2-phenoxybutyric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])(=[O:8])=[O:9])=[CH:11][CH:12]=1
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)CCNS(=O)(=O)c1ccc(N)cc1

Procedure:
To a solution of N-(2-diethylamino-ethyl)-4-nitro-benzenesulfonamide (200 mg, 0.664 mmol) and ammonium formate (377 mg, 5.980 mmol) in EtOH/EtOAc (1/1: 8 mL) under nitrogen was added Pd/C 10% (35.3 mg, 0.033 mmol). The mixture is refluxed overnight until completion of the reaction. After filtration through a celite plug, the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][CH:15]=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:11][CH2:10]2)=[N:13][C:14]([C:28]([F:30])([F:29])[F:31])=[CH:15][CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a mixture of 0.230 g (0.489 mmol) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 2:1 mixture of tetrahydrofuran:methanol (12 mL) is added 0.058 g (2.4 mmol) of lithium hydroxide as a solution in water (2 mL). The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is diluted with water and the pH of the mixture is adjusted to pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate from solution. The formed precipitate is collected by filtration and dried to provide 0.21 g (quant) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C1C=CC=CC=1>[Br-:1].[CH3:7][N:8]1[CH:12]=[CH:11][N+:10]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[CH:9]1
Reactant: Cn1ccnc1
Reactant: N#CCCCBr
Solvent: c1ccccc1
Product: Cn1cc[n+](CCCC#N)c1
Product: [Br-]
Temperature: 60 °C

Procedure:
A mixture of 4-bromobutyronitrile (5.6 g) and 1-methylimidazole (3.0 ml) in benzene (20 ml) was heated to 60° C. for 6 hours. The resulting syrup was separated by decantation, washed with ether and dried to give 4-(3-methyl-1-imidazolio)butyronitrile bromide (7.43 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:3]1.[S:21]([O:26]C)([O:24][CH3:25])(=[O:23])=[O:22]>>[CH3:25][O:24][S:21]([O-:26])(=[O:23])=[O:22].[CH3:1][N+:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:5]([CH3:25])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: COS(=O)(=O)OC
Reactant: Cn1nc(-c2ccccc2Cl)nc1-c1ccccc1Cl
Product: COS(=O)(=O)[O-]
Product: Cn1c(-c2ccccc2Cl)n[n+](C)c1-c1ccccc1Cl
Yield: 189.8 %

Procedure:
The product of Example 1 (15.0 g) and dimethyl sulphate (6.3 g) were heated at 150° C. for 30 minutes. The melt yielded, on crystallisation from petroleum, 20.4 g of desired product, mp 135°-140° C.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[C:49]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52]>>[F:47][C:48]1[C:49]([N:57]2[N:61]=[CH:60][CH:59]=[N:58]2)=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:52]
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cccc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1293284-51-1; 111 mg, 0.54 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17]C(=O)C(F)(F)F)[C:9]=2[CH:24]=[CH:25][CH3:26])=[O:5])[CH3:2].[Se](=O)=O.O>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]1[C:9]=2[CH:24]=[CH:25][CH:26]=[N:17]1)=[O:5])[CH3:2]
Reactant: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc3ncccc3c2o1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To 4-oxo-8-propenyl-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylic acid ethyl ester (3.7 g, 10 mmole) in 100 mL of dioxan was added 4.4 g (40 mmole) of selenium dioxide. The mixture was refluxed under nitrogen for 5 hours. An additional 1.0 g of selenium dioxide was added and reflux continued for 8 hours. After the reaction had cooled, 500 mL of water was added and the mixture was extracted with first 300 mL and then 200 mL of ethyl acetate. The combined organic extracts were washed with water and with saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 2.0 g of the title compound as a yellow solid. An analytically pure sample of yellow solid (m.p. 146-147° C.) was obtained by column chromatography on silica gel with 0-5% ethyl acetate/methylene chloride as eluant.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH2:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH3:11]>C1COCC1>[CH2:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH3:11]
Reactant: CCc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 215 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.339 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-ethylphenoxy)phenyl)pyridin-2-amine (312 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 hr. The mixture was quenched with water at 0° C. Water and EtOAc/THF were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and washed with IPE/EtOAc to give the title compound (295 mg) as a white solid. A part of this was recrystallized from THF/IPE.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:11])=[CH:5][CH:4]=1.I[CH3:39]>CCO>[CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][N:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:36])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[SH:11][CH3:39])=[CH:5][CH:4]=1
Reactant: CI
Reactant: CN(C)c1ccc(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Solvent: CCO
Product: C[SH]=C(NN=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)Nc1ccc(N(C)C)cc1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
A solution containing (E)-N-(4-(dimethylamino)phenyl)-2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (150 mg, 0.285 mmol) and iodomethane (0.054 mL, 0.856 mmol) in EtOH (5 mL) was heated at 80° C. for 3 h before the solvent was removed under reduced pressure. The residue was purified via normal phase flash chromatography (gradient elution with hexanes/EtOAc) to afford the title compound as an orange foam (93 milligrams (mg), 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48 (s, 1H), 8.22 (d, J=8.24 Hz, 2H), 8.17 (s, 1H), 7.89 (d, J=8.24 Hz, 2H), 7.80 (d, J=8.28 Hz, 2H), 7.41 (d, J=8.28 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 6.71 (d, J=8.24 Hz, 2H), 2.99 (s, 6H), 2.42 (s, 3H); EIMS m/z 540 (M+).
Reaction SMILES: [C:1]([C:5]([C:7]1[S:11][C:10]([NH2:12])=[N:9][C:8]=1[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:8]1[N:9]=[C:10]([NH:12][C:18]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[O:25])[S:11][C:7]=1[C:5](=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)C(=O)c1sc(N)nc1-c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
Compound 399 (102 mg, 0.408 mmol) was dissolved in DMF (5 mL), and isonicotinic acid (199 mg, 1.63 mmol), EDC hydrochloride (309 mg, 1.61 mmol) and 1-hydroxybenzotriazole monohydrate (245 mg, 1.60 mmol) were added thereto, followed by stirring at 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 400 (115 mg, 79%) as a pale yellowish green solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][N:21]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate (180 mg, 0.59 mmol) in dichloromethane (10 ml) was added Et3N (202 mg, 2 mmol) and methanesulfonyl chloride (110 mg, 0.98 mmol). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of ice-water (20 ml) and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (0.14 g, 70%).
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:11]23[C:15](=[CH:16][C:17](=[O:18])[C@:9]([OH:20])([CH2:10]2)[CH2:8][C@H:7]1[CH2:21][C:22]([C@H:24]([OH:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:23])[NH:14][CH2:13][C@@H:12]3[OH:19].N1C=CC=CC=1.C(OC(=O)C)(=O)C>CS(C)=O>[CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:11]23[C:15](=[CH:16][C:17](=[O:18])[C@:9]([OH:20])([CH2:10]2)[CH2:8][C@H:7]1[CH2:21][C:22]([C@@H:24]([OH:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:23])[NH:14][CH2:13][C@@H:12]3[OH:19]
Reactant: CC/C=C\C[C@@H]1[C@H](CC(=O)[C@H](O)CCCCCCCC(=O)O)C[C@@]2(O)CC13C(=CC2=O)NC[C@@H]3O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC/C=C\C[C@@H]1[C@H](CC(=O)[C@@H](O)CCCCCCCC(=O)O)C[C@@]2(O)CC13C(=CC2=O)NC[C@@H]3O
Yield: 88 %

Procedure:
To 20 g of FN-1 in 1 L of DMSO, was added 20 ml of dehydrated pyridine and 1 L of acetic anhydride. The solution was allowed to react for 12 hours. The solution was then allowed to settle and the supernatant fluid was removed by decantation. The residual solution containing a solid on the bottom of the beaker was added to a large amount of doubly distilled, deionized water. Next, the solid was filtered, washed with deionized water three times, and then dried to obtain 25 g of a solid of FN-2 (yield: 88%). 3 g of this FN-2 was dissolved in 100 ml of dimethyl sulfoxide, and the solution was poured in a tray and then dried at 60° C. After 12 hours, the polymer was removed to obtain a free standing film.
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][C:3]1=[CH:6][CH:7]=O.C(OCC)(=S)C(N)=O.C(C1[N:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:23]C=1)(C)C>>[CH2:28]([O:27][C:25]([C:22]1[S:23][CH:7]=[C:6]([CH:3]2[CH2:2][CH2:5][CH2:4]2)[N:21]=1)=[O:26])[CH3:29]
Reactant: O=CC=C1CCC1Br
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: CCOC(=S)C(N)=O
Product: CCOC(=O)c1nc(C2CCC2)cs1
Yield: 64 %

Procedure:
4-Cyclobutylthiazole-2-carboxylic acid ethyl ester 265b was synthesized from compound 264b (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) as a yellow oil in 64% yield, following the procedure as described for compound 212. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.32 (t, J=7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J=7.12 Hz, 2H), 7.76 (d, J=0.64 Hz, 1H); MS (ESI, EI+): m/z=212 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:5][O:6][CH:7]([CH2:9][O:10][CH:11]([CH2:13][OH:14])[CH3:12])[CH3:8])[CH3:4].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Zn+2].C1(C)C=CC=CC=1>[C:15]([O:14][CH2:13][CH:11]([CH3:12])[O:10][CH2:9][CH:7]([CH3:8])[O:6][CH2:5][CH:3]([O:2][CH3:1])[CH3:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(C)COC(C)COC(C)CO
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COC(C)COC(C)COC(C)COC(=O)c1ccccc1
Yield: 110.5 %

Procedure:
Tripropylene glycol monomethyl ether (841.6 grams; 3.39 mol), benzoic acid (501.7 grams; 3.46 mol), zinc carbonate 13.5 grams) and toluene (100 ml) were placed into a two liter, three-necked round bottom flask equipped with stirrer, 10" Vigreux column, Dean Stark trap, condenser, heating mantle and thermometer. The reaction temperature was 173° .C at the beginning of the reaction and 235° C. after six hours and 48 minutes. During that time, water (70 ml) was removed. The reaction was continued the next day at 214° C. for an additional three hours and 45 minutes removing additional water (35 ml). Toluene was removed at 65° C. @ 45 mm Hg. The product was washed first with sodium carbonate (170 ml; 15%) at 95°-100° C. for 30 minutes, then with sodium carbonate (22 ml; 15%) and sodium hypochlorite (50 ml), then with sodium carbonate (22 ml; 15%) and sodium hypochlorite (25 ml) with water (300 ml) and finally a second time with water (300 ml). It was dried at 135° C. and filtered to give the desired product (1162.9 grams; 93.6% yield). The product assayed with the following properties:
Reaction SMILES: C(OC([N:8]([C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32].[CH3:36]CN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:36][C:29]1[CH:28]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:24]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH2:8])[C:17]=2[N:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2ccc(Cl)nc12
Reactant: Cc1cccc(CN)c1
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1CNc1ccc2ncnc(N)c2n1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a microwave vial was added tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)carbamate 50-A (0.20 mmol, 76 mg) followed by 3-methylbenzyl amine (2 equiv., 0.4 mmol, 48 mg), DIPEA (3 equiv., 0.6 mmol, 78 mg), and dimethylacetamide (0.5 mL). The reactions were capped and stirred under microwave irradiation for 30 minutes at 130° C. The reaction was then transferred to an 8 ml vial, and concentrated via GeneVac. To the crude material was added dichloromethane (0.25 mL) followed by trifluoroacetic acid (0.5 mL). The reaction was capped and shaken at room temperature for one hour. The reaction was then concentrated, and the crude purified by reverse phase HPLC to yield 11 mg of product. 1H NMR (400 MHz, DMSO) δ 8.16-8.11 (s, 1H), 7.69-7.62 (d, J=9.1 Hz, 1H), 7.53-7.46 (t, J=5.5 Hz, 1H), 7.40-7.33 (m, 1H), 7.22-7.11 (m, 3H), 7.11-7.07 (d, J=9.1 Hz, 1H), 4.70-4.62 (d, J=5.5 Hz, 2H), 2.37-2.33 (s, 3H). LCMS M/Z (M+H)=266.