Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1CCN(C(Cl)=[N+]2CCCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)Cl>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:17][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: ClC(N1CCCCC1)=[N+]1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.8 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)aniline (0.868 g, 3.13 mmol), 4-hydroxybenzoic acid (0.525 g, 3.80 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (1.35 g, 3.74 mmol), and CH2Cl2 (45 mL). This mixture was cooled in an ice bath and diisopropylethylamine (0.96 mL, 5.52 mmol) was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 18 h. The mixture was diluted with EtOAc and washed with 10% aqueous citric acid, water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 100 g of silica gel using 70% EtOAc-hexane as eluant to give 0.57 g of N-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide as a grey solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:17])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Solvent: O=CO
Product: CCOC(=O)C(=NO)c1csc(NC=O)n1
Yield: 76.7 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer)(126.4 g), formic acid (81.3 g) and acetic anhydride (180 g) were treated in a similar manner to that of Preparation 12 to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer)(109.6 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:27])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Yield: 100 %

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9 mg, 0.018 mmol) and potassium carbonate (25.4 mg, 0.184 mmol) in acetone (0.1 ml) is added iodomethane (0.115 ml, 1.840 mmol). After heating at 60° C. for 1 day, the reaction mixture is filtered and concentrated to dryness to afford 2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9.3 mg, 0.018 mmol, 100% yield). MS (ESI) m/z 503.9 (M+1). 1H NMR (400 MHz, CD3CN) δ ppm 8.60 (s, 1H), 7.95 (m, 2H), 7.23-7.18 (m, 2H), 6.79 (br s, 1H), 3.14 (s, 3H), 2.80-2.79 (d, 3H).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[Cl:1][CH2:2][O:3][C:4]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(Cl)OCCl
Reactant: C1COCCN1
Product: O=C(OCCl)N1CCOCC1

Procedure:
Using chloroformic acid chloromethyl ester and morpholine as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1.C(#N)C>C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide, acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0° C. The reaction mixture was stirred for 1 h and then concentrated to remove residual acetic acid. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 60%). LCMS calculated for C15H12BrN4O3 (M+H)+: m/z=375.1, 377.1. found: 375.0, 376.9.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]#[N:29].O>C1COCC1>[C:28]([CH2:27][N:21]1[CH:20]=[C:19]([C:8]2[C:9]3[C:10]([O:17][CH3:18])=[N:11][CH:12]=[C:13]([C:15]#[N:16])[C:14]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:23]=[N:22]1)#[N:29]
Reactant: COc1ncc(C#N)c2c1c(-c1cn[nH]c1)cn2C1CCCC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(C#N)c2c1c(-c1cnn(CC#N)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (152.2 mg) obtained in Step A of Example 98 in THF (2 mL) was added sodium hydride (dispersion in mineral oil, 39.6 mg) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added 2-bromoacetonitrile (38 μL) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over 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 (13.7 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:16][Si:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[C:26](B(O)O)=[CH:25][CH:24]=[N:23]1.O.CCOC(C)=O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][Si:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[C:26]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:25][CH:24]=[N:23]1
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: Oc1ccc(Oc2ccc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc(O)cc2)nc1
Temperature: 100 °C

Procedure:
A suspension of Intermediate E (6.0 g, 23 mmol) and 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-5-boronic acid (SM-2) (6.6 g, 27 mmol) in a mixture of DME (60 mL) and 2N aqueous Na2CO3 (33 mL) is sparged with Argon for 30 minutes. The mixture is treated with tetrakis(triphenylphosphine)palladium(0) (2.6 g, 2 mmol) and heated to 100° C. for 16 hours. The solution is cooled, poured into water/EtOAc, and the organic layer is collected. The aqueous layer is extracted twice with EtOAc, and the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified on SiO2 (EtOAc/heptanes) to provide F.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])[C:8]=2[O:18][CH3:19])=[C:5]([NH2:20])[NH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[OH:30])[CH:25]=O.FC(F)(F)C(O)=O>CO>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[C:12]3[CH:11]=[CH:10][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:8]([O:18][CH3:19])[C:7]=3[C:6]3[C:2]([CH3:1])=[N:3][NH:4][C:5]=3[N:20]=2)[CH:27]=[CH:28][C:29]=1[OH:30]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: COCCOc1cccc(-c2c(C)n[nH]c2N)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCCOc1ccc2c(-c3ccc(O)c(Cl)c3)nc3[nH]nc(C)c3c2c1OC
Product: Cl
Temperature: 70 °C
Yield: 53.1 %

Procedure:
A mixture of 3-methyl-4-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-1H-pyrazol-5-amine (115 mg, 0.42 mmol), 3-chloro-4-hydroxybenzaldehyde (100 mg, 0.64 mmol) and trifluoroacetic acid (3 mL) was heated at 70° C. for 18 hours. The reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic acid eluent). After concentration and lyophillization of the pure fractions a yellow powder was obtained. The solid was dissolved in 4 mL of 1:1 methanol: 4M hydrogen chloride in dioxane, and evaporated to dryness (repeated three times) yielded 2-chloro-4-(1-methyl-9-(methyloxy)-8-{[2-(methyloxy)ethyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrochloride salt (76 mg, 0.17 mmol, 40% yield) 1H NMR (400 MHz, d6-DMSO): 10.82 (b, 1H), 7.80-7.78 (d, 1H), 7.65 (s, 1H), 746-7.44 (m, 2H), 7.18-7.16 (d, 1H), 4.37-4.35 (m, 2H), 3.94 (s, 3H), 3.78-3.76 (m, 2H), 3.36 (s, 3H), 2.83 (s, 3H); MS (EI) for C21H20ClN3O4: 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]([OH:24])[CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1
Reactant: C1CCNCC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(O)CN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and piperidine gave the title compound as yellow oil. MS: 468.1 (MH+, 2Cl).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH:22]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH2:22][NH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Reactant: COC(=O)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](NCc2cc(-n3cnnn3)ccc2OC)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 100 mg of amine from Example 63 in 2 mL of methanol was added 0.040 mL of acetic acid, 1 g of 3A sieves and 94 mg 2-methoxy-5-(1-tetrazolyl)benzaldehyde (prepared according to the procedures given in PCT International Application WO 95/08549, published 30 Mar. 1995; p. 33). The reaction was stirred at room temperature for 30 min and then 0.080 g of sodium cyanoborohydride was added. The reaction was stirred further for 20 h and was then poured into water, made basic with 2N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 3% methanol in methylene chloride to obtain 100 mg of title compound. NMR (CDCl3): δ 1.5 (br s, NH/H2O), 1.8-1.9 (m, 1H), 1.9-2.05 (m, 2H), 2.2-2.35 (m, 1H), 2.24 (m, 1H), 3.3-3.45 (m, 1H), 3.45-3.55 (m, 2H), 3.59 (s, 3H), 3.63 (s, 3H), 3.68 (d, 1H), 6.86 (d, 1H), 6.98 (t, 2H), 7.17 (m, 2H), 7.36 (d, 1H), 7.46 (dd, 1H), 8.85 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])C=O.[C:13]1([OH:19])C=CC=CC=1.Br[CH:21]([F:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[F:27][CH:21]([O:1][C:2]1[CH:3]=[CH:4][C:7]([CH:13]=[O:19])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(F)Br
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Product: CCOC(=O)C(F)Oc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 3-hydroxy-4-nitrobenzaldehyde as the phenol and ethyl 2-bromo-2-fluoroacetate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.07 Hz, 3H), 4.26-4.38 (m, 2H), 6.83 (d, J=55.8 Hz, 1H), 7.76 (dd, J=8.84, 1.26 Hz, 1H), 8.28 (dd, J=8.59, 2.02 Hz, 1H) 8.54 (d, J=2.02 Hz, 1H), 10.02 (s, 1H). ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:23]2=[C:24]3[C:4]4[C:5]([CH:17]=[CH:18][C:19]3=[C:20](S([O-])(=O)=O)[CH:21]=[C:22]2[OH:25])=[C:6](S([O-])(=O)=O)[CH:7]=[C:8](S([O-])(=O)=O)[C:3]=4[CH:2]=1.[Na+:30].[Na+].[Na+].[OH:33][S:34](O)(=[O:36])=[O:35]>O>[OH:25][C:22]1[CH:21]=[CH:20][C:19]2[C:24]3=[C:4]4[C:5]([CH:6]=[CH:7][CH:8]=[C:3]4[C:2]([S:34]([O-:36])(=[O:35])=[O:33])=[CH:1][C:23]=13)=[CH:17][CH:18]=2.[Na+:30]
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1cc2c(O)ccc3ccc4cccc1c4c32
Temperature: 150 °C

Procedure:
Referring to Scheme 6, a 50-mL round bottom flask equipped with a magnetic stirring bar was charged with HPTS (9.5 mmols, 5 g) and 30% H2SO4 (35 mL). The mixture was heated at 150° C. for 20 min and then allowed to cool at ambient temp for 10 min. The solution was poured into 100 g of crushed ice and diluted to 200 mL with water. The mixture was extracted with isopropyl acetate (200 mL×4) and concentrated in vacuo. The residue was mixed with silica gel (3 g) and crushed into a fine powder and dry loaded onto a Biotage 40 M cartridge. The residue was purified via gradient elution using 5% MeOH: (5% NEt3:CH2Cl2) to 15% MeOH:(5% NEt3:CH2Cl2) to give the triethylamine salt of 1 (0.281 g). The salt was treated with 1 M HCl and extracted with isopropyl acetate and the isopropyl acetate layer dried over MgSO4 and concentrated in vacuo to give 1 as a brown/green foam. Synthesis of 1 was reported previously by E. Tietze and O. Bayer 1939 Ann 540:189-210. TLC (MeOH: CH2Cl2:NEt3, 2:7:1) Rf=0.23. 1H NMR (500 MHz, CD3OD) δ 7.94 (t, J=7.6 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 8.02 (d, J=9.2 Hz, 1H), 8.11 (t, J=7.7 Hz, 2H), 8.25 (s, 1H), 8.39 (d, J=9.1 Hz, 1H), 8.98 (d, J=9.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>C1COCC1.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N#Cc1ncccc1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ncccc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A suspension of highly active zinc (Rieke zinc) in THF (100 mg/mL, 12.7 mL, 19.4 mmol) was added via a syringe to a solution of 3-bromo-2-cyanopyridine (1.189 g, 6.497 mmol) in anhydrous THF (20 mL) under an atmosphere of argon. The mixture was stirred for four h at room temperature and then at 50° C. for 15 min. The remaining zinc powder was allowed to settle at the bottom of the flask overnight at −20° C. The top solution was transferred to another flask and cooled to −20° C. To this was added a 1 M solution of copper cyanide di(lithium bromide) complex in THF (6.82 mL) and the resulting mixture was stirred for 5 min at −20° C. and for 35 min at 0° C. and then cooled to −30° C. prior to the addition of 3-bromobenzoyl chloride (1.78 g, 8.12 mmol). The mixture was stirred for 6 h during which time the temperature went from −30° C. to 0° C. The reaction was quenched by the addition of saturated ammonium chloride solution and ethyl acetate was added. The phases were separated and the organic phase was washed with 1 M sodium carbonate solution and with brine. The solution was dried over magnesium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of ethyl acetate in heptane (0-50%) gave 1.18 g (63% yield) of the title compound. 1H NMR (CDCl3) δ 8.92 (dd, 1H), 7.98 (dd, 1H), 7.96 (t, 1H), 7.84-7.81 (m, 1H), 7.73-7.70 (m, 1H), 7.68 (dd, 1H), 7.43 (t, 1H); MS (CI) m/z M+ 287, 289.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.Cl.[CH3:15][N:16]([CH3:21])[C:17](=[O:20])[CH2:18][NH2:19]>C(N(CC)CC)C>[CH3:15][N:16]([CH3:21])[C:17]([CH2:18][NH:19][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:20]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: CN(C)C(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CNCC(=O)N(C)C)c1

Procedure:
By General Procedure A from Ethyl 2-formylpyridine-4-carboxylate, N,N-dimethylglycineamide hydrochloride, and triethylamine. Purification by column chromatography with a gradient of 0-10% MeOH in DCM gave the title product as yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.69 (s, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 4.40 (q, 2H), 4.03 (s, 2H), 3.48 (s, 2H), 2.95 (d, 6H), 1.40 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][C:29]([F:32])([F:31])[F:30])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][C:29]([F:31])([F:30])[F:32])=[C:21]([CH:26]=1)[CH2:20][NH:19][C:12]1[N:11]=[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:7][CH2:6]2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3cc(Cl)ccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(NCc2cc(Cl)ccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-N2-[5-chloro-2-(trifluoromethoxy)benzyl]-5-nitropyrimidine-2,4-diamine (51 mg, 0.1 mmol) in DMF (0.5 mL) was added 1,4-dibromobutane (36 μL, 0.3 mmol) and DIPEA (104 μL, 0.6 mmol). The reaction mixture was stirred at 50° C. for 24 h and then 72 h at room temperature. The reaction mixture was then partitioned between EtOAc (20 mL) and saturated NaHCO3 (less than 1 mL). The organic phase was washed with water (2×2 mL) and dried over Na2SO4. The resulting residue was purified by preparative HPLC to afford 13 mg (25%) of the title compound as a yellow oily solid, m/z 529.3 [M+1]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][CH3:11])=[CH:5][CH:4]=1)#[N:2].[I:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](Cl)=[C:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(O)CC>C(OCC)(=O)C>[I:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:10]([CH3:11])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:26](=[O:28])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(I)cc1
Reactant: CNNc1ccc(C#N)cc1
Solvent: CCOC(C)=O
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(-c2ccc(I)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 55.9 %

Procedure:
A mixture of 29.34 g of 1-(4-cyanophenyl)-2-methylhydrazine, 65.17 g of ethyl 3-(4-iodophenyl)-3-chloro-2-ethoxycarbonylacrylate, 30.9 g of diisopropylethylamine and 300 ml of 1-propanol was refluxed under heating for 17 hours, then cooled and stirred with 200 ml of ethyl acetate at room temperature for 20 hours. The precipitated crystals were collected by filtration and washed with hexane-ethyl acetate to give 42.21 g of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=3)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=2)=[CH:4][CH:3]=1.[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=O)[O:53]C2C=CC=CC=2)[CH:50]=1)([CH3:44])([CH3:43])[CH3:42].C(OC(C)=O)(C)C>CCN(CC)CC>[C:41]([C:45]1[CH:46]=[C:47]([NH:63][S:64]([CH3:67])(=[O:66])=[O:65])[C:48]([O:61][CH3:62])=[C:49]([NH:51][C:52](=[O:53])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[C:22]([CH:36]=[C:37]([C:39]#[CH:40])[CH:38]=4)[C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:24])[N:14]=3)=[CH:4][CH:3]=2)[CH:50]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cc(Nc2nccc(Oc3ccc(N)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Solvent: CC(=O)OC(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product of step (vi) above (175.5 g, 0.324 mol), the product of step (x) above (145.0 g, 0.369 mmol) and iPrOAc (8800 mL). The resulting solution was heated to 60° C. and NEt3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60° C. overnight, following which HPLC analysis indicated 25.77% product of step (vi), 3.60% product of step (x) and 57.85% product of step (xi). Further product of step (x) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60° C. overnight, whereupon HPLC analysis indicated 5.47% product of step (vi), 3.72% product of step (x) and 73.33% product of step (xi). The reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with iPrOAc (2×500 mL). The pink solid obtained was dried, under vacuum, at 40° C. overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. 1H NMR conformed to structure.