Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][S:7]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH3:11])(=[O:9])=[O:8].C([Li])CCC.[CH3:33][C:34]([CH3:36])=[O:35].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][S:7]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][CH:13]=1)([C:34]([OH:35])([CH3:36])[CH3:33])[CH3:11])(=[O:9])=[O:8]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)C(C)c2ccc(C(C)(C)C)cc2)c(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)C(C)(c2ccc(C(C)(C)C)cc2)C(C)(C)O)c(OC)c1
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.01 g of N-[2,4-dimethoxybenzyl]-1-(4-tert-butylphenyl)ethanesulfonamide were initially charged in 20 ml of THF and then, at a temperature of −75° C., 3.23 ml of a 1.6 N butyllithium solution in hexane were added dropwise and the mixture was stirred for 10 minutes. After the addition of 1.16 ml of acetone, the reaction mixture was stirred at constant temperature for 10 minutes. Subsequently, 0.45 ml of trifluoroacetic acid was added and the reaction solution was allowed to come to room temperature. After concentration by rotary evaporation, the crude product was purified using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (484 mg) with a molecular weight of 449.6 g/mol (C24H35NO5S).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=2[F:22])[N:15]=[CH:14][N:13]=1>O1CCOCC1.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[CH:19][C:20]=3[F:22])[N:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1cc(F)c2c(Cl)ncnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1cc(F)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 71.4 %

Procedure:
3-Chloro-4-fluoroaniline (12 g) and 1N HCl in dioxane (40 ml) were added sequentially, each in one portion, to a mixture of 4-chloro-5,7-difluoroquinazoline (16.5 g) in IPA (250 ml) and the mixture was stirred at 80° C. under a nitrogen atmosphere for 17 hours. The reaction mixture was cooled to 0° C. and the precipitated solid was filtered and dried to leave N-(3-chloro-4-fluorophenyl)-5,7-difluoroquinazolin-4-amine as a green solid (18.2 g, 71%); Mass spectrum MH+ 310.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (37 mg, 46%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=2)[CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)nc2ccc(I)cn12
Solvent: ClCCl
Product: Cc1c(CCl)nc2ccc(I)cn12
Reaction time: 4 h

Procedure:
To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (200 mg) in DCM (2 ml) was added thionyl chloride (56 μl) at room temperature, and the mixture was stirred for 4 h. Additional thionyl chloride (125 μl) was added to the reaction mixture, and the mixture was stirred for further 3 h. The reaction mixture was diluted with DCM, and washed with saturated NaHCO3 solution. The DCM layer was separated, dried over Na2SO4 and concentrated in vacuo to give the title compound (150 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
4-Trifluoromethoxy aniline (3.4 g, 19.21 mmol)was dissolved in THF (25 ml) before pyridine (4.44 ml, 54.88 mmol) was added. 4-Acetyl-benzenesulfonyl chloride (4.0 g, 18.29 mmol) was then added as a solid, and the resulting dark solution was stirred for 10 minutes. The volatiles were then removed, and the resulting residue was suspended in THF. Excess Et3N was then added, and the mixture was stirred for several minutes before the solids were filtered. The mother liquor was then evaporated to a solid which was purified by flash chromatography (EtOAc/hexanes) to yield the desired compound as a white solid. (5.5 g (15.31 mmol, 84%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:17](=[O:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 108 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4-Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100° C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108° C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12% aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-(trifluoromethoxy)aniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=10%). MS ISP (m/e): 456.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH:26]=O)[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Yb]>C(Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH:26]=[N:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C=O
Reactant: Nc1ccccc1
Agent: [Yb]
Solvent: ClCCl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C=Nc1ccccc1
Reaction time: 3.5 h
Yield: 51.1 %

Procedure:
100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained.
Reaction SMILES: N([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-].C(OC)(=O)CC>C1(C)C=CC=CC=1>[C:10]([NH:9][CH:5]1[CH2:4][NH:7][C:6]1=[O:8])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCC(=O)OC
Solvent: Cc1ccccc1
Product: O=C1NCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 2.0 g of (3S,4R)-4-azido-3-tritylamino-2-azetidinone in 35 ml of toluene is added 1.14 g of methyl propionate and the mixture is refluxed for 2 hours. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography using n-hexane-ethyl acetate (2:1). The earlier eluate fractions are combined and concentrated under reduced pressure to give 0.818 g of (3S,4R)-[5-methoxycarbonyl)-1,2,3-triazol-1-yl]-3-tritylamino-2-azetidinone (compound A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[CH2:29]([N:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([C:43](O)=[O:44])[C:37]1=[O:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([C:43]([NH:28][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:44])[C:37]1=[O:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: O=C(O)c1cc(Cl)cn(Cc2ccccc2)c1=O
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5cc(Cl)cn(Cc6ccccc6)c5=O)cc4F)c3s2)CC1
Yield: 52 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-benzyl-5-chloro 2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 16.7 mg (52%) of the desired product. LRMS (APCI pos) m/e 642.1, 644.1 (M+1, Cl pattern). 1H-NMR (400 MHz, CD3OD) δ 8.50 (t, 2H), 8.29 (d, 1H), 8.02 (dd, 1H), 7.59 (s, 1H), 7.33-7.48 (m, 7H), 6.71 (d, 1H), 5.32 (s, 2H), 3.67 (s, 2H), 2.56-2.74 (m, 8H), 2.30 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −129.7.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][C:30]([CH3:36])([OH:35])[C:31]([F:34])([F:33])[F:32]>>[F:32][C:31]([F:34])([F:33])[C:30]([OH:35])([CH3:36])[CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:25]
Reactant: CC(O)(CCN)C(F)(F)F
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CC(O)(CCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1)C(F)(F)F

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 4-amino-1,1,1-trifluoro-2-methylbutan-2-ol in a manner similar to that described in Example 11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C(Cc1ccc(F)cc1)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccc(Br)cc2)CC1

Procedure:
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 1.00 g), 1-bromo-4-(bromomethyl)benzene (1.06 g) and potassium carbonate (0.877 g) in dimethylformamide (15 ml) were heated to 70° C., under nitrogen for 1 hour. Water was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was triturated with diethyl ether, filtered and recrystallised from ethanol/water to give water crystalline needles of N-[1-(4-bromobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide. m.p. (+veES) 407 ((M+H)+)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]([CH2:11]CO)[CH2:8][CH2:9]O)[CH3:6].O.C(=O)([O-])O.[Na+].Cl[CH2:21][Cl:22]>>[Cl:3][CH2:9][CH2:8][N:7]([CH2:11][CH2:21][Cl:22])[CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: CCN(CCO)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCN(CCCl)CCCl
Temperature: 0 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
24 ml (330 mmol) of thionyl chloride are added to a solution of 20 g (150 mmol) of 2-[ethyl-(2-hydroxy-ethyl)amino]ethanol in 200 ml of dichloromethane cooled to 0° C. The reaction medium is stirred at ambient temperature for 20 h. After addition of 50 ml of water then gradual addition of a saturated aqueous solution of sodium hydrogen carbonate up to a pH of 7, the reaction medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum. 19.5 g (76%) of bis(2-chloroethyl)ethylamine are obtained in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:21])[CH3:18]>>[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:18]
Reactant: CCNC(=O)Oc1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCNC(=O)Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-ethylamino)carbonyloxy]aniline were reacted to provide N2-[3-[(N-ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (d, 1H, J=3.0 Hz), 7.67-7.55 (m, 2H), 7.24 (t, 1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.07-6.98 (m, 2H), 6.84-6.79 (m, 2H), 6.67 (m, 2H), 6.60 (d, 1H, J=7.5 Hz), 5.22-5.14 (m, 1H), 3.36-3.27 (m, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CDCl3): −47012; LCMS: purity: 99%; MS (m/e): 384 (MH+).
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1/[CH:24]=[CH:25]/[C:26]([CH3:28])=[O:27]>>[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[CH:24]=[CH:25][C:26]([CH3:28])([OH:27])[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: CCOC(CC(C)=CC=CBr)OCC
Product: CCOC(CC(C)=CC=CC(C)(O)C=CC1=C(C)CCCC1(C)C)OCC
Yield: 73 %

Procedure:
The procedure is as in Example 1, but employs 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (0.56 g; 2.12 mmol) and β-ionone (0.33 g; 1.716 mmol, i.e. 0.8 equivalent). After flash chromatography, 9-(2,6,6-trimethyl-1cyclohexenyl)-1,1-diethoxy-3,7-dimethyl-7-hydroxy-3,5,8-nonatriene, or C20 diethyl hydroxyacetal, (0.47 g) is obtained. The yield is 73%. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.Cl[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:10]=[C:4]2[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: O=C(CCl)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc2nc(C(F)(F)F)cn12
Temperature: 120 °C

Procedure:
5 g (28.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 6.26 g (42.7 mmol) of 3-chloro-1,1,1-trifluoropropanone are dissolved in 200 ml of DMF and heated at 120° C. for 16 h. After the reaction is complete, water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the product is purified by silica gel chromatography. Drying under high vacuum results in 3.5 g (45% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.C([O:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH:21]=[O:22])=O)(C)(C)C>C1COCC1>[CH3:23][C:20]1([CH3:24])[CH:21]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:22][C:17](=[O:16])[NH:19]1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A cold (−78° C.), stirred solution of (trimethylsilyl)acetylene (4.42 g, 45.0 mmol) in anhydrous THF (20 mL) was treated with nBuLi (18 mL, 45.0 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde (2.80 g, 15 mmol) in anhydrous THF (20 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water. After removal of THF, the residue was partitioned between ether (150 mL) and water (100 mL). The separated organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to give the crude 4,4-Dimethyl-5-trimethylsilylethynyl-2-oxazolidinone (100%) as yellow oil which was carried to the next step.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23.B(Br)(Br)[Br:30].ClCCl.Br>ClCCCl.CO>[BrH:30].[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23
Reactant: BrB(Br)Br
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(OC)cc1-2
Agent: Br
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(O)cc1-2

Procedure:
A solution of 98 g (0.222 mol) of 5-amino-N,N-diethyl-9-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine dihydrochloride (Compound 1A), in 900 ml 1,2-dichloroethane, was treated with 444 ml of a 1M solution of boron tribromide in dichloromethane (0.444 mol). The mixture was heated to 50° C. for 24 hours at which time 200 ml of the boron tribromide solution (0.200 mol) were added, and the reaction maintained at 50° for an additional 24 hours. The mixture was cooled, and methanol (600 ml) was carefully added. The mixture was heated under reflux for three hours, then cooled at 0° for 48 hours. The yellow precipitate was collected by suction filtration, washed with cold methanol, then dried at 60°, 200 mm Hg, affording 110.4 g of 5-amino-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazol-9-ol, hydrobromide with 1.8 equivalents of hydrogen bromide, mp 305° (decomposition), 98.36% pure by HPLC.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[N:5][N:4]([CH:8]2[N:12]([CH2:13][C:14]#[C:15][I:16])[C:11](=[O:17])[CH2:10][CH2:9]2)[N:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH2:23][N:24]=[N+:25]=[N-:26]>>[Br:7][C:6]1[C:2]([Br:1])=[N:3][N:4]([CH:8]2[N:12]([CH2:13][C:14]3[N:26]=[N:25][N:24]([CH2:23][C:22]4[CH:27]=[CH:28][CH:29]=[C:20]([C:19]([F:18])([F:31])[F:30])[CH:21]=4)[C:15]=3[I:16])[C:11](=[O:17])[CH2:10][CH2:9]2)[N:5]=1
Reactant: O=C1CCC(n2nc(Br)c(Br)n2)N1CC#CI
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: O=C1CCC(n2nc(Br)c(Br)n2)N1Cc1nnn(Cc2cccc(C(F)(F)F)c2)c1I

Procedure:
Synthesized from 5-(4,5-dibromo-2H-1,2,3-triazol-2-yl)-1-(3-iodoprop-2-ynyl)pyrrolidin-2-one and 3-trifluoromethyl-benzylazide using general procedure; 0.663 g, 0.982 mmol, 93%; mp=105-110° C. (dec.); IR (υ[cm−1]) 3002, 2104, 1696, 1415, 1327, 1166, 1123, 1074, 921, 829, 753, 702; 1H NMR (600 MHz, CDCl3) δ=7.59 (d, J=7.8, 1H), 7.56 (s, 1H), 7.48 (t, J=7.7, 1H), 7.40 (d, J=7.7, 1H), 6.16 (d, J=7.6, 1H), 5.59 (d, J=3.3, 2H), 4.88 (d, J=15.7, 1H), 3.92 (d, J=15.7, 1H), 2.95-2.86 (m, 1H), 2.65-2.56 (m, 1H), 2.49 (dd, J=17.1, 9.9, 1H), 2.43-2.36 (m, 1H); 13C NMR (151 MHz, CDCl3) δ=175.0, 147.0, 135.1, 131.6 (m), 131.5, 129.9, 126.1, 125.8 (m), 125.1 (m), 123.9 (m), 79.6, 78.3, 53.9, 36.4, 28.6, 25.6; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C17H14Br2F3IN7O, 673.8618; found 673.8613.