Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(O)(=O)[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])O.[H][H].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>OCC(CO)O>[C:6]([OH:8])(=[O:7])[C:4]([CH2:9][C:10]([OH:12])=[O:11])=[CH2:3]
Reactant: [H][H]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: OCC(O)CO
Product: C=C(CC(=O)O)C(=O)O
Temperature: 204 °C
Reaction time: 1 h

Procedure:
The process of WO2010/059925 was reworked as follows (derived from Examples 1 and 12): 20 grams of glycerol reagent grade and 40 grams of citric acid monohydrate were mixed The mixture was brought under nitrogen to a temperature of 140° C. while stirring, and kept under nitrogen at that temperature for a period of one hour. The resulting prepolymer was heated to 204° C. for a period of one hour. Uncontrollable foaming took place resulting in an inhomogeneous foam. The material discolored to yellow and had poor mechanical properties. Combustion analysis showed a carbon content of 43.76% and a hydrogen content of 5.56%, showing that about 5-10% of the citric acid decarboxylated to form itaconic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21](I)[CH:22]=2)=[N:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([C:35]2[O:36][CH:37]=[CH:38][C:39]=2[CH3:40])=[O:34])[CH:29]=[CH:30][CH:31]=1)#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[N:15][C:14]([C:17]2[CH:22]=[C:21]([C:25]#[C:24][C:26]3[CH:27]=[C:28]([NH:32][C:33]([C:35]4[O:36][CH:37]=[CH:38][C:39]=4[CH3:40])=[O:34])[CH:29]=[CH:30][CH:31]=3)[CH:20]=[N:19][CH:18]=2)=[N:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(-c3nnn(CCCO[Si](C)(C)C(C)(C)C)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the nitrogen bubbled solution of 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine (89 mg, 0.2 mmol, 1 eq), N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (67.5 mg, 1.5 eq), triphenylphosphine (1.3 mg, 0.025 eq), and triethylamine (0.09 mL, 3 eq) in anhydrous DMF (2 mL) was added bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.1 eq), and copper(I) iodide (8 mg, 0.2 eq). After the reaction mixture was stirred at room temperature for 20 minutes, it was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was loaded onto silica and columned (EtOAc-Hex 1:20 to 1:4). The fractions containing the desired product were collected, concentrated to a lesser amount, and the white fluffy solid was filtered giving N-(3-((5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-methylfuran-2-carboxamide in an the amount of 78 mg.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[CH2:16]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
23.7 g (150 mmole) 1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 120 ml absolute dimethylformamide under a nitrogen atmosphere. After adding 7.9 g of 50% sodium hydride in mineral oil (165 mmole), the mixture was stirred for 1 hour at 20° C. After adding 14.3 ml allyl bromide (165 mmole), the mixture was heated to 70° C. and stirred for 1 hour. Thereafter it was treated with 160 ml water and was extracted at 10° C.-15° C., three times with ether, once with water and once with saturated sodium chloride solution. After removing the solvent by distillation, 24 g of crude product (81% theoretical) were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(CO)c1)C2=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C=O)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
(S)-5-(3-Hydroxymethylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (100 mg, 0.280 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), and the mixture was stirred overnight at room temperature after adding manganese dioxide (366 mg, 4.21 mmol). The mixture was filtered through sellite, and the filtrate was collected, concentrated, and purified by silica gel column chromatography to give (S)-5-(3-formylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (77.8 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[O-])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[S:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[S:30][C:31]1[CH:32]=[C:33]([NH:34][C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[CH:3]=2)=[O:15])[CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C([O-])Nc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(F)c4)c3)c2cc1OC

Procedure:
Following the procedure described in Example 138B with 3-fluoro-4-(trifluoromethyl)phenylcarbamate as described in Example 150 (135 mg, 0.45 mmol) and using 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol). To this mixture diisopropylethyl amine (58 mg, 0.45 mmol) and DMAP (3.7 mg, 0.03 mmol) the reaction was heated at 50° C. overnight. The reaction was concentrated to dryness and triturated with dichloromethane. The resulting solid was collected by vacuum filtration to give 156 mg. 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.10 (s, 1H), 8.79 (s, 1H), 7.8 (s, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.35 (m, H), 7.25 (m, 4H), 4.00 (s, 6H). LCMS (ESI) m/z 519 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1.Br[CH:16]([CH3:29])[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=1[Cl:28])=O>CN(C=O)C>[Cl:28][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[C:23]([CH3:25])=[CH:24][C:19]=1[C:17]1[N:14]=[C:12]([C:9]2([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:11][CH2:10]2)[O:13][C:16]=1[CH3:29]
Reactant: COc1cc(Cl)c(C(=O)C(C)Br)cc1C
Reactant: NC(=O)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2nc(C3(c4ccc(Cl)cc4Cl)CC3)oc2C)cc1C
Temperature: 80 °C

Procedure:
1-(2,4-Dichloro-phenyl)-cyclopropanecarboxylic acid amide (46 mg, 0.2 mmol) and 2-Bromo-1-(2-chloro-4-methoxy-5-methly-phenyl)-propan-1-one (58 mg, 0.2 mmol) were combined in DMF (1 mL) at 0.2 M and the mixture heated to 80° C. overnight. The reaction was then cooled to room temperature. The desired product was purified by reversed phase HPLC/MS using an acetonitrile/water gradient and C18 stationary phase. Yield: 1 mg (2%) [MH]+ 424.2, 422.2, 426.0 (small).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[C:11](=[O:19])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(COC)OC>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:16]=2)[C:11](=[O:19])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(Cc2ccccc2)c2cc(Br)ccc12
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=c1[nH]nc(Cc2ccccc2)c2cc(-c3ccncc3)ccc12

Procedure:
A suspension of EXAMPLE 1E (75 mg, 0.24 mmol), pyridin-4-ylboronic acid (44 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)aaduct with dichloromethane (19.4 mg, 0.024 mmol) and potassium carbonate (66 mg, 0.48 mmol) in a mixture of 7:3:2 dimethoxyethane:water:ethanol (3 mL) was heated in a Biotage Initiator microwave at 150° C. for 20 minutes. The volatiles were removed, and the residue was purified by HPLC (Zorbax C-18, 0-100% gradient acetonitrile in water containing 0.1% trifluoroacetic acid) to yield the title compound. MS (ESI) m/z 314 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 4.44 (s, 2H), 7.20 (d, J=7.14 Hz, 1H), 7.27-7.33 (m, 2H), 7.34-7.40 (m, 2H), 7.95 (d, J=6.35 Hz, 2H), 8.22-8.28 (m, 1H), 8.32-8.41 (m, 2H), 8.78-8.84 (m, 2H), 12.68 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[N:12]([CH2:21][CH2:22][NH:23][CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>>[CH3:32][N:33]([CH3:38])[S:34]([N:23]([CH3:24])[CH2:22][CH2:21][N:12]1[C:13]2[C:18](=[N:17][CH:16]=[CH:15][CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:26]=[CH:27][C:2]([F:1])=[CH:3][C:4]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[C:11]1=[O:25])(=[O:36])=[O:35]
Reactant: CNCCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)N(C)CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21
Temperature: 25 °C

Procedure:
A solution of N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.07 g, 0.16 mmol) in DM (3 mL) was treated with dimethylsulfamoyl chloride (0.44 g, 0.31 mmol) and Hunig's base (0.11 mL, 0.62 mmol) and stirred at room temperature for several hours. Additional dimethylsulfamoyl chloride was added after an hour. The reaction was injected directly onto a reverse phase HPLC column and the compound collected after eluting with a gradient of 95% water/acetonitrile to 5% water acetonitrile. The fractions were combined, evaporated and the crude oil was lyophilized from acetonitrile and water to give the product as a fluffy solid.
Reaction SMILES: [CH3:1][C:2]1[N:17]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH2:16]2)=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].I[CH2:29][CH3:30]>>[CH2:29]([N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[CH2:6][C:5]3[N:17]([CH2:16][C:8]1=2)[C:2]([CH3:1])=[C:3]([C:22]([O:24][CH3:25])=[O:23])[C:4]=3[C:18]([O:20][CH3:21])=[O:19])[CH3:30]
Reactant: CCI
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1[nH]c3ccccc3c1C2
Agent: [H-]
Agent: [Na+]
Product: CCn1c2c(c3ccccc31)Cc1c(C(=O)OC)c(C(=O)OC)c(C)n1C2

Procedure:
This compound was prepared from dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (5.1 g, 15 mmol), NaH (0.54 g, 22.5 mmol) and iodoethane (2.3 g, 15 mmol). Yield 5.1 g (92%); mp 202-203° C. 1H NMR (DMSO-d6) δ 1.29 (3H, t, J=6.9 Hz, Me), 2.46 (3H, s, Me), 3.73 (3H, s, COOMe), 3.74 (3H, s, COOMe), 4.17 (2H, s, CH2), 4.20 (2H, q, J=6.9 Hz, CH2), 5.29 (2H, s, CH2), 7.05-7.09 (1H, m, ArH), 7.16-7.20 (1H, m, ArH), 7.49-7.51 (1H, m, ArH), 7.53-7.55 (1H, m, ArH). Anal. Calcd for (C21H22N2O4): C, 68.84; H, 6.05; N, 7.65. Found: C, 68.46; H, 6.06; N, 7.59.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=12.ClC1C(=O)[C:25](C#N)=[C:26]([C:31]#[N:32])C(=O)C=1Cl.C(N)CC>C1COCC1>[CH2:31]([NH:32][C:15]1[C:2](=[O:1])[C:3]2[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=2[C:5]2[C:14]=1[S:13](=[O:17])(=[O:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[N:6]=2)[CH2:26][CH3:25]
Reactant: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCCN
Solvent: C1CCOC1
Product: CCCNC1=C2C(=Nc3ccccc3S2(=O)=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 62.8 %

Procedure:
To a suspension of 5-hydroxy-12H-benzo[a]phenothiazine-7,7-dioxide (594 mg) in THF (10 ml) was added 2,3-dichloro 5,6-dicyano-1,4-benzoquinone (1.021 gram). The mixture was stirred at room temperature for 2 minutes, then there was added n-propyl amine (0.2 ml). The stirring was continued for 0.5 hour, then the mixture was evaporated to dryness. To the residue was added 50 ml dichloromethane and the mixture was stirred for 15 minutes and filtered. The filtrate was evaporated to dryness and the residue crystallized from a mixture of toluene and hexane to afford the title compound (442 mg) as a red-brown crystalline solid, m.p. 149°-151° C. (dec.).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[CH2:2][CH3:3]
Reactant: N#C[O-]
Reactant: CCCc1ccc(Cc2cccc(N)c2)n1CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(Cc2cccc(NC(N)=O)c2)n1CCC
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A stirred solution of 2 g (7.7 mmol) of 1,5-dipropyl-2-(3'-aminobenzyl)pyrrole in 200 ml of benzene was treated with 1 g (15.3 mmol) of sodium cyanate followed by the dropwise addition, over a 11/2 hour period, of a solution of 1.5 ml (19 mmol) of trifluoroacetic acid in 100 ml of benzene. The reaction mixture was stirred at room temperature for 1 more hour, poured into 300 ml of saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3×300 ml). The combined extracts were washed with water (2×300 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 100 g of silica gel, using hexane-ethyl acetate (55:45) as eluant, thus obtaining 1.85 g (83%) of the title compound, 1,5-dipropyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane. M.P. 123°-126° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9]Br)=[C:7]([C:11]#[N:12])[C:6]([CH2:13]Br)=[C:5]([C:15]#[N:16])[C:4]=1[CH2:17]Br)#[N:2].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([CH2:9][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])=[C:7]([C:11]#[N:12])[C:6]([CH2:13][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])=[C:5]([C:15]#[N:16])[C:4]=1[CH2:17][P:19]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:26])#[N:2]
Reactant: N#Cc1c(CBr)c(C#N)c(CBr)c(C#N)c1CBr
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1c(C#N)c(CP(=O)(OCC)OCC)c(C#N)c(CP(=O)(OCC)OCC)c1C#N)OCC

Procedure:
A solution of 1,3,5-tricyano-2,4,6-tris(bromomethyl)benzene (1.0 g, 2.3 mmol) and P(OEt)3 (1.6 g, 14 mmol) in 60 mL of toluene was refluxed for 4 hrs. The solvent was removed in vacuo and the product was purified by column chromatography with hexane/ethyl acetate (10/1) as the eluent to obtain colorless oil. Yield, 0.97 g (69%); IR 2299 (CN), 1263 (P═O); 1H NMR δ 4.21 (q, 12H, J=7.2), 3.73 (d, 6H, J=22.1) 1.32 (t, 18H, J=7.2).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:7]=1)=[CH2:5])C>C1COCC1.O>[C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:28][CH2:29][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]3)=[N:23][CH:22]=2)[CH:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(C)=O)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Ethyl 1-[5-[7-(1-ethoxyvinyl)-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate was dissolved in THF (24 mL) and water (6 mL). Sulfonic acid resin MP (200 mg, 3.2 mmol/g) was added and the reaction stirred at rt for 1 h, after which time LCMS indicated clean conversion to the ketone. The reaction mixture was filtered and the solvent removed in vacuo to give a solid which was triturated with Et2O to give the desired product as a yellow solid (600 mg, 64% yield over 2 steps).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1=[O:39]>C1(C)C=CC=CC=1>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=1[N:31]1[C:32](=[O:39])[CH2:33][N:34]([CH2:9][C@H:7]([NH:8][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]2[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1
Reactant: CC1(C)CN(c2c(F)cccc2F)C(=O)CN1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 98.8 %

Procedure:
A solution of 600 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (1.84 mmol) and 574 mg of 1-(2,6-difluorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (60d) (2.40 mmol) in toluene (18 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 1.03 g of the title compound (yield: 99%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](O)(=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCO
Temperature: 135 °C
Reaction time: 5 h

Procedure:
To a solution of 24.4 g (0.4 mole) ethanolamine in 500 ml ethanol at 60° C. was added 85.2 g (0.3 mole) stearic acid. The ethanol was distilled off until the pot temperature reached 100° C., at which time 300 ml toluene was added, and the water was distilled off as an azeotrope. After 5 hours at 110° C., 6 ml water was recovered in the Stark & Dean trap. Some toluene was removed to raise the pot temperature to 135° C. After an additional 4 hours, another 7 ml water was trapped. The title product (38.5 g) that crystallized on cooling had a melting point of 96°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])[CH3:2]>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:11]1=[O:24])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1cnc(C)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1cnc(C)nc1
Reaction time: 1.5 h

Procedure:
To stirred solution of 5-3 (180 mg) in methanol (8 mL) was added a suspension of 10% Pd on carbon (60 mg) in ethanol (1 mL). The resulting suspension was stirred under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through Celite. The solvent was evaporated to give 5-4 as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:21](=[O:24])[CH2:22][CH3:23])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
400 mg (2 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide (Example 1b) are dissolved in 15 ml dichloromethane, cooled in the ice-bath and treated with 0.36 ml triethylamine. 185 mg (2 mmol) propionyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 489 mg (96%) of the desired product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[CH3:23][C:24]1[N:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[CH:28]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:31]2[CH2:32][CH2:33][CH:29]([N:27]3[CH:28]=[C:24]([CH3:23])[N:25]=[N:26]3)[CH2:30]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Yield: 46.5 %

Procedure:
5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (298 mg, 1 mmol) was reacted with 470 mg (2.5 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in the presence of 380 mg (2.5 mmol) of DBU in 20 ml of dry acetonitrile for two days under reflux conditions and the atmosphere of nitrogen. The yellow suspension was then evaporated to dryness and to the residue water was added. The yellow solid was filtered and crystallized repeatedly (3x) with acetonitrile to free the product from the unreacted starting material. After drying, 200 mg of the desired product was obtained, m.p. 271°-272.5° C. 1H NMR (TFA) δ: 9.15 (s, 1H), 8.4 (s, 1H), 5.8-5.6 (m, 1H), 4.8-4.05 (m, 5H), 3.0-2.7 (m, 2H), 2.67 (s, 3H), 1.65-1.2 (m, 4H). Anal. calcd. for C20H20F2N6O3.1/2 H2O: C, 54.67; H, 4.82; N, 19.12. Found: C, 54.91; H, 4.69; N, 18.76.