Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(C(F)(F)F)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-trifluoromethylpyridine.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(C(C)=O)C(C)C>[C:1]([O:4][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CC(=O)COC(C)=O
Temperature: 5 °C

Procedure:
A solution of 1.204 l (21.0 moles) of glacial acetic acid and 2.786 l (20.0 moles) of triethylamine in 8.75 l of methyl isobutyl ketone is heated under reflux, and a solution of 1.498 l (11.2 moles) of ethyl 4-chloro-3-oxobutyrate in 1.75 l of methyl isobutyl ketone is added at the boiling point in the course of 20 minutes. When the addition has ended, the mixture is heated under reflux for a further 30 minutes and cooled to about 5° C. and the salts which have precipitated out are filtered off. The residue on the filter is washed with 4.5 l of methyl isobutyl ketone. The combined filtrates are concentrated in vacuo, and first 2 l of drinking water and then 4 l of a 9% strength sodium bicarbonate solution are added to the residue. The suspension is extracted three times with 4 l of ethyl acetate each time and the combined extracts are dried over 2 kg of sodium sulphate, filtered and concentrated in a rotary evaporator at a bath temperature of 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1Br

Procedure:
A mixture of 2-(3-bromo-4-methylphenyl)-1,3-benzoxazole (240 mg, 0.83 mmol), n-bromosuccinimide (180 mg, 0.99 mmol), and benzoyl peroxide (10 mg, 0.041 mmol) in carbon tetrachloride (15 mL) was refluxed for 3 h. The white precipitate was filtered and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography on silica gel eluting with EtOAc:hexane (1:5) to afford 2-[3-bromo-4-(bromomethyl)phenyl]-1,3-benzoxazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaT (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][N:15]([C:31](=[O:33])[CH3:32])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ncc3n2CN(C(C)=O)c2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (100 mg) and diisopropylethylamine (50 ml) in THF (20 ml) is added acetyl chloride (50 ml) and the mixture stirred at RT for 5 hours. The reaction is extracted with ethyl acetate (200 ml), the solvent evaporated, and the residue is purified by preparative-plate chromatography (75% ethyl acetate/hexane) to afford 3-(4-methoxyphenyl)-5,6-dihydro-6-acetylimidazo[1,5-c]-quinazoline (Compound 49) as a light yellow solid. m.p. 80°-82° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])=[N:17][CH:18]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:22])=[N:17][CH:18]=1
Reactant: C1CCNC1
Reactant: CC(Cl)C(=O)Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccc(Br)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.01 g (29.0 mmol) K2CO3 and 1.19 mL (14.5 mmol) pyrrolidine are added successively to a solution of 3.5 g (13.3 mmol) N-(5-bromo-pyridin-2-yl)-2-chloro-propionamide in 50 mL DMF. The reaction is stirred for 3 days at RT and combined with 150 mL water. The aqueous phase is extracted twice with EtOAc and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: PE/EtOAc 4:6 after EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][O:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:19]([C@H:18]([CH3:20])[C:17]([O:16][CH3:15])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: COC(=O)[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol) and D-alanine methyl ester (4 g, 0.04 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (330 g of silica gel, 0-50% EtOAc/Hexane) to give a yellow solid. MS m/z 277.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (377 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-70% EtOAc in heptane) to give a pure product (110) as a white semisolid (680 mg, 86%).
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH:14]([NH2:17])([CH3:16])[CH3:15]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:13])[NH:17][CH:14]([CH3:16])[CH3:15])[CH3:9])[CH3:12]
Reactant: CCOC(C)=NOCCC(=O)OC
Reactant: CC(C)N
Solvent: CO
Product: CCOC(C)=NOCCC(=O)NC(C)C
Temperature: 55 °C
Reaction time: 14 h
Yield: 13 %

Procedure:
To a known compound, 3-(1-ethoxy-ethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 300 mg, 1.585 mmol) were added methanol (3 ml) and isopropylamine (1.4 ml), and the mixture was stirred at 55° C. for 14 hours. Additional isopropylamine (1.0 ml) was added, and the mixture was stirred for 3 hours using a focused microwave synthesis system (Discover™, CEM) at 100 W. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(2-isopropylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (46 mg, 13% yield).
Reaction SMILES: Cl.[C:2]1(/[C:8](/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH3:29])=[CH:21][CH:20]=2)=[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[CH2:10]CO)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([Cl:53])(Cl)(Cl)Cl>C(#N)C>[Cl:53][CH2:49][CH2:10][C:9]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH3:29])=[CH:21][CH:20]=1
Reactant: CNCCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CNCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 41.0 g of (Z)-1,2-diphenyl-1-[4-[2-(N-methylamino)ethoxy]phenyl]-1-buten-4-ol hydrochloride, 57.4 g of triphenyl phosphine, 61.6 g of carbon tetrachloride and 500 ml of acetonitrile is refluxed for 1 h. On cooling the product crystallizes out and is collected for filtration. The yield of the hydrochloride is 25.3 g (59%) and m.p. 206°-8° C. The base is liberated from its salt by conventional means giving an oil.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:13][C@H:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:15]2)[CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.N>ClCCl.CO>[NH2:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C@H:12]3[CH2:11][C@H:10]([CH2:9][OH:8])[CH2:13]3)[N:15]=[C:16]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:28][CH:29]=3)[C:17]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1
Agent: ClB(Cl)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](CO)C1
Temperature: -78 °C
Reaction time: 7 h

Procedure:
A solution of trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.244 g, 0.00051 mol) in dichloromethane (10 mL) was cooled to −78° C. and a solution of 1.0 M boron trichloride in dichloromethane (1.53 mL, 0.00153 mol) was added dropwise, keeping the temperature less than −70° C. The reaction mixture was stirred seven hours at −78° C., after which time a 8 M solution of ammonia in methanol (1.5 mL) was added. The solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (93:7). The solvent was removed in vacuo to give to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutylmethanol (0.192 g, 0.00049 mol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[I:9]I.OO>C1CCCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(Br)cc1
Agent: OO
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 150.5 %

Procedure:
To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equiv, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0 equiv, Qualigens) and the mixture was heated at 50° C. After 30 min, the reaction mixture became homogenous. 30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was added to the reaction mixture. The reaction was heated for 4 h at 50° C. The reaction was cooled to room temperature, diluted with ethyl acetate (5.0 L) and washed with aqueous sodium-sulphite (2.5 Kg in 4.0 L) solution. The organic layer was washed with water (3.0 L) and brine (3.0 L) dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate and hexanes) to get 4-bromo-2-iodoaniline (650 g, 75.0%), as off white solid. TLC solvent system: 100% hexanes. Product's Rf: 0.6. MS (ESI, positive ion) m/z: 297.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.09 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-l-(tert-butoxycarbonyl)piperidine (711 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:25](=[O:27])[CH3:26])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
Add a solution of {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g, 3.66 mmol) in dichloromethane (25 mL) dropwise to a solution of acetyl chloride (0.35 g, 4.50 mmol) in dichloromethane (125 mL) at room temperature. Upon complete addition of the amine, add triethylamine (0.74 g, 7.32 mmol) and a crystal of DMAP to the reaction and stirred at room temperature for 18 hours. Add an additional 65 uL of acetyl chloride to the reaction and stir an additional 2 hours. Pour the reaction into saturated aqueous sodium bicarbonate then extract with dichloromethane (3×100 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 1.3 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g): 1H NMR (CDCl3, 300.00 MHz): 8.00 (s, 1H), 7.49 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.98-6.89 (m, 4H), 4.69 (s, 1H), 3.37 (d, 2H, J=6.2 Hz), 2.77 (t, 2H, J=7.0 Hz), 2.18 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[C:16]([F:27])[CH:15]=2)[CH2:9]1)=O)CCC.[NH3:28]>CO>[F:27][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@H:8]([C:6]([NH2:28])=[O:5])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[S:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=1
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (Step 6, 0.300 g, 0.758 mmol) is dissolved in 2M ammonia in methanol solution (8 ml) and stirred overnight at room temperature. The reaction is concentrated under vacuum and purified by PTLC (10% methanol/CH2Cl2) to give the title compound as a white solid (0.22 g, 87%), mp 249-251° C.; 1H NMR (300 Mhz, CDCl3) δ 3.59 (s, 2H), 4.04 (dd, 1H), 4.30 (t, 1H), 5.05 (dd, 1H), 7.49-7.72 (m, 4H), 7.88 (br s, 1H), 11.63 (s, 1H); MS (m/z) for C13H11FN4O4S: [M+H]+=339.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([Cl:14])=[N:12][OH:13]
Reactant: ON=CCCc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)CCc1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 3-(2,6-dichlorophenyl)propanal oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added. The resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (1.05 g, 86%). 1H NMR (DMSO-d6): 11.67 (s, 1H), 7.45 (d, J=8 Hz, 2H), 7.28 (t, J=8 Hz, 1H), 3.17-3.13 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5](=[N:8][N+:9]([O-:11])=[O:10])SC)(=[O:3])[CH3:2].[NH2:12][CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1>C(#N)C>[C:1]([NH:4][C:5]([NH:12][CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1)=[N:8][N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CSC(=N[N+](=O)[O-])NC(C)=O
Reactant: NCc1cnc(Cl)s1
Solvent: CC#N
Product: CC(=O)NC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a mixture of 0.22 g of N-acetyl-S-methyl-N'-nitroisothiourea and 5 ml of acetonitrile was dropwise added 0.2 g of 5-(aminomethyl)-2-chlorothiazole at -2° C. Stirring was continued at the same temperature for additional 1 hour, and then the reaction mixture concentrated. The residue solidified was recrystallized from ethanol to give 0.31 g of N-actyl-N'-(2-chloro-5-thiazolylmethyl)-N"-nitroguanidine (reference compound No. 5), mp 132°-133° C. NMR (CDCl3): 2.33(3H, s), 4.68(2H, d, J=6 Hz), 7.50(1H, s), 9.60(1H, br), 11.85(1H, br).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[S:23][C:22]([NH:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[N:21][C:20]=3[NH2:44])[O:16][N:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)=O.C(OCC)C>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[S:23][C:22]([NH2:24])=[N:21][C:20]=3[NH2:44])[O:16][N:15]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2noc(-c3sc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N)n2)c1
Solvent: CCOCC
Solvent: O=CO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(-c3sc(N)nc3N)n2)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of 1.3 mmol of (3-{5-[4-amino-2-(trityl-amino)-thiazol-5-yl]-[1,2,4]oxadiazol-3-yl}-phenyl)-carbamic acid tert-butyl ester, prepared as described in Example B(1), dissolved in 8 ml of 1:1 formic acid/diethyl ether was stirred at room temperature until the starting material had been consumed by TLC (typically 5 h). The resulting light yellow solution was stripped of all solvent in vacuo, heated gently under high vacuum to remove residual formic acid, and then recrystallized from methylene chloride, giving 255 mg of the title compound (53% yield) as a light-yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:29])=[C:4]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:5]([O:21][CH3:22])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.[CH3:30][N:31](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH3:22])=[C:4]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[C:3]([CH3:29])=[C:2]([CH:7]=3)[C:30]#[N:31])[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C)c1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C#N)c(C)c1-c1cnn(C)c1
Temperature: 120 °C
Yield: 27 %

Procedure:
Pre-formed catalyst (0.05 mL, from Example 40) was added to a mixture 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.7 mg, 0.019 mmol), zinc (0.54 mg, 0.0082 mmol) and zinc cyanide (2.2 mg, 0.019 mmol) in N,N-dimethylacetamide (0.3 mL). The mixture was degassed with nitrogen 3 times. The reaction was heated at 120° C. for 1.5 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.1 mg, 27%). The product was isolated as a single enantiomer. LCMS calculated for C21H23N8O (M+H)+: m/z=403.2; Found: 403.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[NH:12])[NH:10][OH:11])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=O>C1(C)C=CC=CC=1>[C:14]([C:19]1[O:11][N:10]=[C:9]([C:4]2[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:12]=1)([CH3:18])([CH3:15])[CH3:13]
Reactant: N=C(NO)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2cnc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
5,6-Dichloro-N-hydroxy-3-pyridinecarboximidamide (3.0 g, 0.015 mol) was slurried in toluene (30 mL) and trimethylacetyl chloride (1.93 g, 0.016 mol) added. The mixture was stirred at room temperature for one hour and then heated under reflux conditions for four hours. This was then cooled and filtered through Celite, washing with additional toluene (20 mL). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (0-10% ethyl acetate:hexane) gave the desired product as a white solid (2.77 g, 68%).