Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Ic1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (16.5 g) and acetic acid (11.7 ml) were added to a solution of 4-iodoaniline (30 g) in dioxane (500 ml), and the resulting mixture was stirred for 13 hours while heating the mixture to reflux. The reaction solution was cooled to room temperature and saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting the resulting mixture 4 times with ethyl acetate. Organic layers were washed 3 times with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=4/1). The product was recrystallized from dichloromethane/hexane mixed solvent to obtain N-(4-iodophenyl)pyrimidin-2-amine (22.27 g). NMR (H1, CDCl3): δ 6.73 (1H, t, J=4.6 Hz), 7.18 (1H, brs), 7.40-7.42 (2H, m), 7.59-7.61 (2H, m), 8.41 (2H, d, J=4.6 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8](=O)[CH2:9][O:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:40])=O>CC(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][N:7]1[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=2[O:10][CH:9]=[C:8]1[Cl:40]
Reactant: O=C1COc2cc(Cl)ccc2C(=O)N1
Reactant: ClCCCCBr
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)c1ccccc1
Solvent: CC(C)=O
Product: O=C1c2ccc(Cl)cc2OC=C(Cl)N1CCCCCl
Temperature: 90 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
918 mg of 8-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 20 ml of acetone, 1.2 g (2 equivalents) of potassium carbonate and 819 mg (1.1 equivalents) of 1-bromo-4-chlorobutane were added, and the mixture heated and refluxed for 7 hours. The resultant mixture was allowed to cool, then filtered. The filtrate was condensed and the residue obtained was dissolved in 2 ml of phosphorus oxychloride. Further, 1.4 ml (2 equivalents) of N,N-diethylaniline was added and the mixture was stirred at 90° C. for 12 hours. The phosphorus oxychloride was distilled off and a 10% sodium hydroxide aqueous solution added under ice cooling. The mixture was extracted with methylene chloride, then was washed with a saturated aqueous solution of potassium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off and the crude product obtained was purified by silica gel column chromatograph (hexane:ethyl acetate=6:1) to obtain 598 mg of the above-identified compound (yield 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C(O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:32])=CC=1.[CH2:42]([N:44]([CH2:47]C)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:42][N:44]=[C:47]=[O:32])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CCN(CC)CC
Reactant: CCCCCCCC(C(=O)O)C1=C(C)C(=O)C(OC)=C(OC)C1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCN=C=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 10 ml of toluene is dissolved 1.4 g of 2,3-dimethoxy-6-methyl-1,4-benzoquinon-5-yl-n-nonanoic acid, and 1.09 g of DPPA and 0.62 ml of triethylamine are added. The mixture is stirred at room temperature for 3 hours. The reaction mixture is promptly extracted with ether and ice-water. The ether layer is taken, dehydrated and concentrated to 5 ml. The product is heated under reflux for 3 hours to give a toluene solution of the contemplated product isocyanate.
Reaction SMILES: [Li:1]CCCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>C1COCC1>[CH3:6][Si:7]([CH3:14])([CH3:13])[N-:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[Li+:1]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A solution of lithiumhexamethyl disilazide was prepared by adding 4.8 ml of 1.6 m BuLi in hexanes to a solution of 1.8 ml of hexamethyldisilazane in 10 ml of dry THF at −40° C. This solution was stirred for 15 min at −40° C. A quantity of 7.8 ml of this solution was added dropwise to a solution of 1.34 g of compound 13 in 20 ml of dry THF at −70° C. The mixture subsequently stirred at −70° C. for an additional hr and then poured into 50 ml of sat. NH4Cl solution and extracted with ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:35]=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[O-:37]Cl=O.[Na+].CC(O)(C)C.O>CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: Cn1cc([C@H]2CC[C@H](N3CCN(c4cc(C=O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cn1cc([C@H]2CC[C@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21

Procedure:
The trans was obtained by the process described for Example 73 by combining 0.30 g (.60 mmol) 8-[4-[(Trans)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarbaldehyde, 0.48 g (5.5 mmol) NaClO2, 0.48 g (4.1mmol) NaH2PO4, 24 mL t-BuOH, 3 mLCH3CHC(CH3)2, and 6 ml water. The product fractions were pooled, striped, and treated with 54 mg (0.60 mmol) of (CO2H)2 in absolute EtOH to give 97 mg (.16 mmol, a 10% yield) mp: 275° C. MS (ES) m/z: 494 (MH)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:23][C:24]([F:38])([F:37])[CH2:25][C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:20])([CH3:21])[C:16]([F:18])([F:17])[F:19])=[C:9]([C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([CH2:25][C:24]([F:38])([F:23])[F:37])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:12])[CH:13]=1)(=[O:4])=[O:3]
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 27 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid (Example A14) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 27%). MS (m/e): 560.3 (M+H+, 100%).
Reaction SMILES: C1C(Cl)=CC=C(Cl)C=1.Cl[C:10]1[CH:11]=[C:12]([C:19]([O-:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O.[Na+].[OH-].[Na+]>O.CN1C(=O)CCC1>[C:19]1(=[O:20])[O:21][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:10][CH:11]=[C:12]12
Reactant: O=C([O-])c1cc(Cl)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Clc1ccc(Cl)cc1
Product: O=C1OC(=O)c2ccccc21
Temperature: 255 °C

Procedure:
Then, 1116.5 g (7.59 moles) of p-dichlorobenzene, 1540.2 g of NMP and 32.7 g of water were fed to react the contents at a temperature of 220° C. for 4.5 hours. Thereafter, 282 g (15.7 moles) of water, 175.9 g (0.790 mole) of sodium hydrogen 4-chlorophthalate and 31.32 g (0.783 mole) of sodium hydroxide were additionally introduced under pressure in the autoclave. The contents were heated up to 255° C. to react them for 5 hours.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[C:1]([N:62]1[CH2:63][CH2:64][N:59]([C:56]2[CH:57]=[CH:58][C:53]([C:45]3[NH:44][C:43](=[O:65])[C:42]4[C:47](=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:41]=4[O:40][CH3:39])[N:46]=3)=[CH:54][CH:55]=2)[CH2:60][CH2:61]1)(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccncc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of isonicotinic acid (0.083 g, 0.68 mmol) in THF (20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCl (0.141 g, 0.74 mmol), Et3N (0.10 mL, 0.74 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g, 0.68 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.110 g, 34%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.58-8.79 (m, 2H), 8.12 (d, J=9.0 Hz, 2H), 7.45 (d, J=6.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.64-4.06 (m, 9H), 3.22-3.54 (m, 5H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].[Br:39]N1C(=O)CCC1=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH:7]([Br:39])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Under an atmosphere of nitrogen, a solution of 3.4 g of (5Z,13E)-(9α,11α,15S)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)prosta-5,13-dienoic acid methyl ester in a mixture of 30 ml of methylene chloride and 6 ml of N,N-dimethylformamide was added dropwise to a suspension of 1.35 g of N-bromosuccinimide in 50 ml of methylene chloride at -20° to -10° C. and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was then poured into ice-water and extracted with diethyl ether. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (4:1) as eluent to give 3.43 g of the title compound having the following physical characteristics:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12].O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(F)c(Br)c1
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (0.075 g) was added to a stirred solution of 3-bromo-4-fluorobenzaldehyde (1.2 g) in dry tetrahydrofuran (20 cm3), the temperature being maintained below 5° C. by external cooling. The temperature of the reaction mixture was then allowed to rise to the ambient value (ca 20° C.) and the mixture was stirred for 2 hours; GLC analysis of a withdrawn sample indicated 82% conversion at this time, and further lithium aluminium hydride (0.025 g) was therefore added to the mixture. After a further 1.5 hours GLC analysis indicated that the reaction was complete. The mixture aas poured into water (20 cm3) and the products extracted into diethyl ether (3×20 cm3). The combined ethereal extracts were washed with brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave the title compound in high purity.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.BrC1SC([CH2:35][N:36]2C3C(=CC=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)=CC=1>>[O:28]=[C:9]1[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:5]1[O:6][C:2]([C:35]#[N:36])=[CH:3][CH:4]=1
Reactant: O=C1N(Cc2ccc(Br)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1N(Cc2ccc(Br)o2)c2ccccc2C12COc1cc3c(cc12)OCO3
Product: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1

Procedure:
Following the procedure described in EXAMPLE 10.79, and making non-critical variations using 1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-[(5-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (44%) as a colorless solid: mp 167-169° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 1H), 7.21-7.17 (m, 1H), 7.12-7.08 (m, 1H), 7.07-7.03 (m, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.44 (d, 1H), 6.08 (s, 1H), 5.86 (q, 2H), 4.96 (ABq, 2H), 4.78 (ABq, 2H); MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:25]=[O:27])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C=Nc1cc(Oc2ncccn2)c(Cl)cc1F

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy) benzenamine (2 g) and triethyl amine (1.7 g) were dissolved in anhydrous ethyl acetate (75 ml) and stirred under ice cooling. Triphosgene (2.5 g) dissolved in ethyl acetate (75 ml) was slowly added to the stirred solution. The solution was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isocyanatophenoxy)-pyrimidine which was used for the next step without further purification.
Reaction SMILES: N12CCCN=C1CCCCC2.C(O[C:15](=[O:31])[CH:16]([C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30])[C:17]([O:19]CC)=O)C.Cl.[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]([NH2:41])=[NH:40].Cl>CN1CCCC1=O.O>[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]1[N:41]=[C:15]([OH:31])[C:16]([C:22]2[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[C:17]([OH:19])[N:40]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1cnccn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 95 °C
Reaction time: 7 h
Yield: 76 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 14.4 g, 0.0944 mol) is added to a mixture of 2-(2,4,6-triflorophenyl)malonic acid diethyl ester (14.3 g, 0.0472 mol) and pyrazine-2-carboxamidine hydrochloride (9.00 g, 0.0566 mol) in 1-methyl-2-pyrrolidinone (NMP; 50 mL) solvent. The resulting mixture is heated to 95° C. while stirring for 7 hours. The mixture is cooled to about 50° C. and then HCl solution (37%, 5.6 mL) is added dropwise, keeping the temperature below 50° C. The mixture is then allowed to cool to about 20° C. Water (50 mL) is added dropwise over 20 minutes, causing the product to precipitate as a solid from the mixture (20-25° C.). The solid is collected by filtration, and the product cake is washed with water (300 mL). The solid is allowed to dry at 23° C. under atmospheric pressure for 24 hours, giving a yellow solid (11.5 g, 97% HPLC area, 76% yield. 1H NMR (DMSO-d6): d 12.45 (bs, 2H), 9.41 (s, 1H), 8.91 (s, 1H), 8.46 (m, 1H), 7.23 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH:24]1([O:8][C:6]2[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OC1CCCCC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OC2CCCCC2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, cyclohexanol and DBU in DME. ES-MS m/e (%): 305 (M+H+, 100), 223 ([M+H—C6H10]+, 80).
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.C(OC([NH:18][C:19]([C:22]1[O:27][C:26](=[O:28])[C:25]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]=1)([CH3:21])[CH3:20])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:18][C:19]([C:22]1[O:27][C:26](=[O:28])[C:25]2[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=2[N:23]=1)([CH3:21])[CH3:20]
Reactant: Cc1cccc2nc(C(C)(C)NC(=O)OC(C)(C)C)oc(=O)c12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc2nc(C(C)(C)N)oc(=O)c12

Procedure:
250 ml of a 50% trifluoroacetic acid-methylene chloride solution was added dropwise under ice-cooling to 5.63 g of 2-{1-[(tert-butoxycarbonyl)amino]-1-methylethyl}-5-methyl-4H-3,1-benzoxazin-4-one with stirring. The mixture was stirred at 0° C. for 0.58 hour, and concentration of the mixture gave a residue which was dissolved in 80 ml of a 4N hydrochloric acid-1,4-dioxane solution at 0° C. After stirring for 0.58 hour, the reaction mixture was subjected to azeotropic distilation with toluen so as to give the hydrochloride salt of 2-(1-amino-1-methylethyl)-5-methyl-4H-3,1-benzoxazin-4-one. To the salt was added 4.47 g of 9-fluorenyloxyacetic acid, and dissolved in 180 ml of N,N-dimethylformamide. To the mixture were added successively at room temperature 2.2 ml of N-methylmorpholine, 2.98 g of 1-hydroxybenzotriazole and 5.09 g of a water-soluble carbodiimide hydrochloride. After stirring for 18 hours, the reaction mixture was concentrated to give a residue which was purified by a silica gel column chromatography (eluting solution: methylene chloride-ether), followed by recrystallization from methylene chloride-ether to give 6.34 g of 2-{1-[(9-fluorenyloxyacetyl)amino]-1-methylethyl}-5-methyl-4H-3,1-benzoxazin-4-one: mp 162.1°-162.8° C. (see Table 1).
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14].[CH:32]([O-:35])([CH3:34])[CH3:33].[Na+]>O>[CH:32]([O:35][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:35][CH:32]([CH3:34])[CH3:33])[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14])([CH3:34])[CH3:33]
Reactant: CC(C)[O-]
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ccc(S(C)(=O)=O)c(OC(C)C)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2F)CC1

Procedure:
0.27 mmol of 2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 4.15) was added to a solution of sodium isopropanolate (prepared by dissolving 3 mmol of sodium in 2 ml of isopropanol). The reaction mixture was heated under reflux for 5 hours, cooled, diluted with water and extracted with ethyl acetate, yielding the title compound as a slightly yellow solid. MS (m/e): 557.3 (MH+, 66%)
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN(C)C=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 168 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of dimethyl formamide. The stirred mixture is heated to reflux (168° C.) and held 15 minutes; then cooled to about room temperature. Then 150 ml 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried overnight in a vacuum oven. There is obtained 11.4 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 81.2% pure, or a 59.7% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][C:31]=1[CH2:32][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: O=Cc1cc(CCO)ccc1Cl
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4Cl)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.294 g) in NMP (2 mL) was treated with acetic acid (0.039 mL) and stirred for 5 minutes. A solution of 2-chloro-5-(2-hydroxyethyl)benzaldehyde (example 61, step c) (0.189 g) in NMP (3 mL) was then added, the resulting solution was stirred for 1 hour and was then treated with sodium triacetoxyborohydride (0.217 g). The mixture was stirred overnight at room temperature, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.238 g.