Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8](F)=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].[CH2:16]([O:23][C:24]([C:26]1[CH:32]=[CH:31][C:29]([O-:30])=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[K+].[K]>CN(C)C=O>[CH2:16]([O:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:30][C:8]2[C:7]([F:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=2[C:2]([F:1])([F:15])[F:14])=[CH:31][CH:32]=1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Reactant: Fc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(F)c(F)c2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
35.4 g of octafluorotoluene (0.15 mol) are dissolved in 400ml of dimethylformamide, the solution is cooled to 0øC using a cryostat, and a solution of 40 g of potassium 4-benzyloxycarbonylphenoxide (0.15 mol) in 300 ml of dimethylformamide is then added dropwise over the course of 2 hours. After 2hours at 0° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, the residue is taken up in a little tetrahydrofuran, and the solution is filtered through a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off through a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@@H:3]1[OH:13].C(=O)(O)[O-].[Na+].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(OC)(C)(C)C>O1CCCC1.O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][C@H:3]([OH:13])[C@H:2]2[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: N[C@H]1c2cc(Br)ccc2OC[C@@H]1O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(N[C@H]1c2cc(Br)ccc2OC[C@@H]1O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 221.5 %

Procedure:
To a suspension of (3R,4S)-4-amino-6-bromo-chroman-3-ol (692 g, 2.84) and sodium bicarbonate (476 g, 5.67 mol) in tetrahydrofuran (3.0 L) and water (3.0 L) at 17° C. add 4-fluorobenzoyl chloride (369 mL, 3.12 mol) dropwise via addition funnel over 15 min. and stir for 2 hr. Add water (2 L) and methyl tert-butyl ether (3.5 L) and stir for 5 min. Separate the organic phase and wash it with water (2 L) and brine (2 L). Dry the organic portion over anhydrous magnesium sulfate and concentrate in vacuo to obtain a pale yellow solid (2.3 kg). Triturate the solid in heptane (5 L) at 25° C. for 3 h. Collect by filtration and dry in an oven at 50° C. for 12 hr. to obtain the title compound (975 g, 94%) as a white solid. LC-ES/MS m/z (79Br/81Br) 366/368 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 0.0025 mol) and allowed to stir r for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.151 g, 0.0012 mol) was added and stirred for further 3 h at 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.025 g, 16% yield). 2,8-Dimethyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrid [4,3-b]indole (0.025 g, 0.000078 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0098 g, 0.00007 8 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 47% yield).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[C:18]([CH3:34])=[N:19][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([N:28]5[CH2:32][CH2:31][CH2:30][C@@H:29]5[CH3:33])[CH2:24]4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>CO.CCO>[ClH:37].[CH3:34][C:18]1[C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:35][CH2:36][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:16])=[CH:22][CH:21]=[C:20]([N:23]2[CH2:27][CH2:26][C@@H:25]([N:28]3[CH2:32][CH2:31][CH2:30][C@@H:29]3[CH3:33])[CH2:24]2)[N:19]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCNCC2)C1=O
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of 2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) in methanol (2 mL) was added a saturated solution of HCl in EtOH (2 mL) and stirred the resulting mixture for 20 hours. Concentrated the reaction mixture and dried under high vacuum to afford 42 mg (97% yield) of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]4)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ccc2cc(N)ccc2n1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc2cc(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc2n1

Procedure:
The title compound was prepared from 45C by procedures analogous to those described in Experiment 2E and 2F. HPLC: 100% at 1.81 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].Br[CH2:28][CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:28][CH2:29][OH:30])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCO
Reaction time: 6 h
Yield: 79.8 %

Procedure:
To a solution of the compound of Example 32 (1.00 g, 2.85 mmol) in isopropanol (10 mL) and 3 M aq. NaOH (3 mL), 2-bromo-ethanol (1.42 g, 11.4 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of 2-bromo-ethanol (176 mg, 1.41 mmol) is added. Stirring is continued at 60° C. for 6 h. The mixture is diluted with EA and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to 3:1 to give the title compound (900 mg) as a colourless oil; LC-MS: tR=1.10 min, [M+H]+=396.09.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:25][N:26]([CH3:28])[NH2:27]>>[CH3:25][N:26]([CH3:28])[NH:27][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN(C)C)n(C)n1
Yield: 100 %

Procedure:
As described for example 43, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (120 mg, 0.37 mmol) was converted using N,N-dimethylhydrazine instead of rac-3-aminotetrahydrofuran, to the title compound (130 mg, 100%) which was obtained as a colorless oil. MS: m/e=356.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20].O=O.S([O-])([O-])(=O)=[O:34].[Ca+2]>C(C(Cl)(F)F)(Cl)(Cl)F>[F:30][C:2]1([F:1])[O:34][C:3]1([F:29])[C:4]([F:27])([F:28])[O:5][C:6]([F:26])([F:25])[C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[O:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)([O-])[O-]
Agent: O=O
Agent: [Ca+2]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Fc1c(F)c(F)c(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C2(F)OC2(F)F)c(F)c1F
Temperature: 0 °C
Yield: 31 %

Procedure:
A 100-ml metal tube lined with stainless steel and charged with 105.3 g (0.22 mol) of perfluoro(7-phenoxy-4-oxa-1-heptene) was heated at 140° while oxygen was pressured in intermittently until no pressure drop was observed. The liquid product mixture was fractionated to afford 78.5 g of distillate, bp 37°-70° (3 min). The distillate was shaken with 1 liter of ice water, and then 25 ml of CFCl2CF2Cl and some calcium sulfate were added to hasten separation. The lower layer was dried over calcium sulfate and fractionated to give 33.3 g (31%) of perfluoro(7-phenoxy-1,2-epoxy-4-oxaheptane), bp 55° (1.9 mm). IR (CCl4): 6.47 (epoxide ring), 6.58 (aromatic C=C), 8-9μ (CF, C-O). NMR (CCl4): 19F -84.1 (m, 2F, OCF2), -84.6 (m, 2F, OCF2), -129.0 (s, 2F, CF2), -151.8 (m, 2F, arom. CF), -155.1 (t, JFF 21.0 Hz, 1F, arom. CF), -156.6 (t, JFF 17.9 Hz, 1F, ring CF), and -161.7 ppm (m, 2F, arom. CF), with AB groupings at -7382, -7534, -7566, and -7719 Hz (m, 2F) for CF2 adjacent to epoxide ring and at -10381 and -10424 Hz (d of t, JFF 18.8, 9.8 Hz, 1F) and --10600 and -10642 Hz (d, JFF 17.3 Hz, 1F) for epoxide CF2.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=S)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: S=C1Nc2cc(Cl)c(Cl)cc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: Clc1cc2c(cc1Cl)Nc1ccccc1C(NCc1cccnc1)=N2
Yield: 53.4 %

Procedure:
A solution of 329 mg (1.1 mmol) of 7,8-dichloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.2 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (97/3) followed by recrystallization from acetone/H2O gave 217 mg (52.8% yield) of the product as a yellow solid, mp 209-210° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =370.
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2].[C:33]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](O)=[O:43])([OH:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])[C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:42]([CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][C:33]([OH:35])=[O:34])=[O:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Reactant: O=C(O)COCCOCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCNC(=O)COCCOCC(=O)O

Procedure:
25 is prepared similarly to 24 starting from 500 mg of 2,3,4-triacetoxy-1-{2-[2-(2-aminoethoxy)ethoxy]acetyl}-5-hydroxypentyl acetate 23, 927 mg of (2-carboxymethoxyethoxy)acetic acid, 400 μl of diisopropylcarbodiimide and 288 mg of hydroxybenzotriazole in 20 ml of methylene chloride. This gives 25:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[O:22]([C@@H:29]1[CH2:33][NH:32][C@H:31]([CH2:34][O:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:32]3[CH2:33][C@@H:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][C@H:31]3[CH2:34][O:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2)cc1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 101.1 %

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (351 mg, 1.07 mmol), methyl 4-((2S,4S)-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (303 mg, 1.07 mmol), EDC•HCl (308 mg, 1.61 mmol), HOBt (218 mg, 1.61 mmol) and triethylamine (0.74 ml, 5.35 mmol) was stirred at room temperature for 21 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 40 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (640 mg, 100%) was obtained as a yellow oil.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>>[F:24][C:23]([F:26])([F:25])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[N:7]=[N:8][C:3]([NH:2][C:15](=[O:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [Cl-]
Product: CCCCCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 6, making variations only as required to use hexyanoyl chloride in place of phenoxyacetyl chloride to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (30% yield). 1H NMR (300 MHz, CDCl3) δ 11.65, 8.62, 7.75, 7.65, 7.58, 7.46-7.53, 7.37, 4.08, 3.88, 3.52-3.78, 3.30-3.40, 2.63, 1.72-1.79, 1.24-1.40, 0.90. MS (ES+) m/z 449.7 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH2:13][C:14]#[CH:15])([C:8]([O:10]CC)=[O:9])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>O.C(O)C>[CH3:1][C:2]([CH2:13][C:14]#[CH:15])([C:3]([OH:5])=[O:4])[C:8]([OH:10])=[O:9]
Reactant: C#CCC(C)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCC(C)(C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
187 g (0.88 mol) of diethyl 2-methyl-2-propargyl-malonate are added to a solution of 101 g (1.8 mol) of potassium hydroxide in a mixture of 560 ml of water/ethanol (1:1) and the mixture is refluxed with stirring for 2 hours. After the reaction has ended (monitored by TLC) the mixture is evaporated to dryness in vacuo and the residue is then taken up with in water. The aqueous solution is acidified with 50% sulphuric acid and extracted several times with methylene chloride. The combined extracts are dried, evaporated to dryness in vacuo and a colourless product is obtained, m.p. 135° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9](OCC)(OCC)(OCC)[CH2:10][CH3:11]>>[CH2:10]([C:11]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1)[CH3:9]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#C/C(N)=C(/N)C#N
Product: CCc1nc(C#N)c(C#N)[nH]1
Yield: 82.6 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 53.3 g of diaminomaleonitrile and 91.3 g of triethyl orthopropionate. 59.5 g of the title compound were obtained as crystals, melting at 179°-181° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([O:32]CC)=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH:20]C(OC(C)(C)C)=O)[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[C:5]([CH3:36])[C:4]=1[F:37].[OH-].[Na+]>>[NH2:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([OH:32])=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[C:5]([CH3:36])[C:4]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)c(C)c2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)c(N)c(Cl)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Reaction time: 8 h
Yield: 43.1 %

Procedure:
12N Hydrochloric acid (5 ml) was added to ethyl 7-amino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.75 g), and the mixture wags stirred overnight while heating under reflux. After the reaction mixture was allowed to cool, it was neutralized with a 20% aqueous solution of sodium hydroxide, arid solids deposited were collected by filtration. The solids were washed with ethanol and dried to obtain the title compound (570 mg) as a pale brown powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:16][CH3:17])=[C:10]([CH:15]=1)[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:16][CH3:17])=[C:10]([CH:15]=1)[CH2:11][OH:12]
Reactant: COCCCc1ccc(SC)c(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCc1ccc(SC)c(CO)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 5-[3-(methyloxy)propyl]-2-(methylthio)benzoate (1 eq.) from the previous step was taken up in THF (0.1 M) and then added lithium aluminum hydride (1 eq.). The reaction mixture thus obtained was stirred at RT for 16 h. The reaction was then quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(C(C)(C)C)ccc(C(C)(C)C)c5s4)cc3CC[C@@H]12
Yield: 17.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-di(t-butyl)benzothiazole (130 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 33 mg (17%) of the title compound as an amorphous foam. FDMS: m/e=506.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(Cl)cc3Cl)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 9.3 mg (13% of theory) of the product are obtained starting from 60 mg (0.15 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 23A) by couping with 29.3 mg (0.15 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: C([Li:5])CCC.[CH3:6][N:7]([CH3:15])[C:8]1[C:9]([CH3:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>CCCCCC.C(OCC)C>[CH3:6][N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Li:5]
Reactant: [Li]CCCC
Reactant: Cc1ccccc1N(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]Cc1ccccc1N(C)C

Procedure:
To a mixture of 23 ml of a 1.6 M solution of butyllithium in hexane and 10 ml of ethyl ether was added 5.0 g of N,N-dimethyl-o-toluidine with stirring. The mixture gradually became yellow and overnight a pale yellow solid was deposited. It was separated by filtration and dried, to give 2.0 g of 2-dimethylaminobenzyllithium.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1)#[N:2].[OH-:19].[K+].Cl>C1COCC1>[C:1]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1)(=[O:19])[NH2:2]
Reactant: [OH-]
Reactant: CCOC(=O)c1nc(C#N)sc1-c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(=O)O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate in THF was added a 1 M aqueous KOH solution, followed by stirring at room temperature for 12 hours. To the reaction mixture was added 1 M hydrochloric acid, and the solid precipitated was collected by filtration to obtain 2-carbamoyl-5-phenyl-1,3-thiazole-4-carboxylic acid as a pale yellow solid.