Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:45][CH2:44][C:43]2([CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:47]2[CH2:48][CH2:49][C:43]3([CH2:44][CH2:45][N:41]([CH3:40])[CH2:42]3)[CH2:46]2)[N:8]=1
Reactant: CN1CCC2(CCNC2)C1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNc2nc(N3CCC4(CCN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 4 %

Procedure:
In DCM (30 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (429 mg, 0.96 mmol) and DIEA (0.22 mL, 1.12 mmol). 2-Methyl-2,7-diazaspiro[4.4]nonane (154 mg, 1.1 mmol) was then added. The reaction was conducted at ambient temperature overnight. The solvent was removed by rotary evaporation, followed by addition of water and extraction with ethyl acetate. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1) to give a white solid (20 mg, 4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether using 0.18 equivalent of water of crystallisation and melts at 140°-143°.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C@H:7]([NH:9]C(=O)OC(C)(C)C)[CH3:8])[O:4][N:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([C@H:7]([NH2:9])[CH3:8])[O:4][N:3]=1
Reactant: Cc1noc([C@@H](C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc([C@@H](C)N)n1
Reaction time: 16 h
Yield: 151.9 %

Procedure:
To a solution of tert-butyl [(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (6.0 g, 26.4 mmol) in dioxane (40 mL) was added 4 M hydrochloric acid in dioxane (30 mL). The reaction mixture was stirred for 16 h. The solution was concentrated and dried by vacuum to give hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (5.1 g). 1H NMR (500 MHz, CD3OD): δ 490-4.83 (m, 1H); 2.41 (s, 3H); 1.72 (d, J=7.0 Hz, 3H). MS 128.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]4[O:20]C(C)(C)C(C)(C)[O:17]4)=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([B:16]([OH:20])[OH:17])=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: OB(O)c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Yield: 138.4 %

Procedure:
7.93 g of 2-(4-chlorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine are dissolved in 200 ml of acetone and 100 ml of water; 223 ml of 1N hydrochloric acid are added thereto, dropwise there with stirring, and the mixture is stirred at ambient temperature for 16 h. The reaction mixture is subsequently concentrated under reduced pressure. 4.78 g of compound are obtained, which compound is used as is in the following stages.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[C:39](#[N:41])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([C:39]#[N:41])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(C#N)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1 was treated with tetra-n-butyl ammonium cyanide in acetonitrile at 100° C. for 4 hours. Solvent was concentrated to dryness and purified by chromatography to give a protected intermediate that was de-protected similar to step 5, Example 76, to give 4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2-carbonitrile. MS: ES+: 399
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([OH:20])=[C:15]([Br:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH2:22]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:23]1[O:25][CH2:24]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:27]([O:26][CH2:22][CH:23]([OH:25])[CH2:24][O:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([C:10]([C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH2:24][CH:23]([OH:25])[CH2:22][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:15]([Br:21])[CH:14]=2)([CH3:12])[CH3:11])=[CH:5][C:6]=1[Br:9])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOCC1CO1
Reactant: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1c(Br)cc(C(C)(C)c2cc(Br)c(OCC(O)COCCCC)c(Br)c2)cc1Br

Procedure:
2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane (i.e., tetrabromobisphenol A) (136 g; 0.25 mole), butyl glycidyl ether having an epoxide content of 7.45 equiv./kg (67.1 g; 0.5 equiv.), and benzyltrimethylammonium chloride (0.5 g) were stirred at 120° C. for 1 hour and at 150° C. for 41/2 hours. The mixture had a residual epoxide content of 0.01 equiv./kg, indicating that the reaction was substantially complete.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.[F:14][CH:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1Br)[F:16]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH:15]([F:14])[F:16])=[C:19]([C:7]2[C:6]([O:12][CH3:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:20]=1
Reactant: FC(F)Oc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(OC)cn1
Product: COc1cc(-c2cc(Cl)ccc2OC(F)F)c(OC)cn1

Procedure:
417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and 494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluoromethyl ether in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (purity 90%, 27% of theory)
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14](=[O:34])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[N:16]=2)=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14](=[O:34])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[N:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(c1ccc(CN2N=C(c3ccc(Cl)cc3)OCC2=O)cc1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(c1ccc(CN2N=C(c3ccc(Cl)cc3)OCC2=O)cc1)C1CCCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
86 mg (2.04 mmol) of lithium hydroxide monohydrate were added to a solution of 450 mg (1.02 mmol) of methyl (4-{[2-(4-chlorophenyl)-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl]methyl}phenyl)(cyclopentyl)acetate in 10 ml of dioxane and 10 ml of water, and the mixture was stirred at 80° C. for 12 h. After removal of the dioxane under reduced pressure, the aqueous phase was adjusted to pH 2 using 1 M hydrochloric acid, which resulted in the flocculation of the product. The solution was filtered and the filter residue was dried under reduced pressure. This gave 373 mg (0.87 mmol, 86% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1Cc1ccccc1
Reactant: O=C(Cl)CCCBr
Product: O=C(CCCBr)Nc1ccccc1Cc1ccccc1

Procedure:
2-benzylaniline and 4-bromobutyryl chloride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].N[NH:11][C:12]([NH2:14])=[S:13].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:11][C:12]1[S:13][C:4]([CH2:3][CH2:2][NH:1][CH2:6][CH2:7][C:8]2[S:13][C:12]([NH2:14])=[N:11][N:9]=2)=[N:5][N:14]=1
Reactant: N#CCCNCCC#N
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCNCCc2nnc(N)s2)s1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A mixture of 3,3′-iminodipropionitrile (1.50 g, 12.18 mmol) and thiosemicarbazide (2.22 g, 24.36 mmol) in TFA (10 mL) was heated at 85 for 4.5 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5-(2-((2-(5-amino-1,3,4-thiadiazol-2-yl)ethyl)amino)ethyl)-1,3,4-thiadiazol-2-amine (1005, 1.47 g). 1H NMR (300 MHz, DMSO-d6) δ 6.95 (s, 4H), 2.90 (d, J=6.0 Hz, 4H), 2.83 (d, J=6.3 Hz, 4H).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12]C1C=CC(C(=O)C)=CC=1>>[OH2:9].[F:12][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH:10]=[O:11])=[O:9])=[CH:3][CH:4]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Solvent: O
Product: O=CC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared using essentially the same procedure as described by H. A. Riley and A. R. Gray in Organic Synthesis, Collective Volume II, p. 509 for the preparation of phenylglyoxal hydrate, but using 4′-fluoroacetophenone in place of acetophenone.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OC2CCC1N(S(=O)(=O)c1ccc(O)cc1)C2
Yield: 104.6 %

Procedure:
A mixture of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (1.0 g, 2.7 mmol), ethyl acetate-methanol (1:1, 100 mL) and 10% Pd on charcoal (0.22 g) was shaken under 50 psi of hydrogen for 1.5 h. Filtration through a pad of Celite and concentration of the filtrate in vacuo afforded 0.80 g of 5-(4-hydroxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless solid.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Br:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[Br:8][C:4]1[N:3]([O:2][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: On1ccnc1Br
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)On1ccnc1Br)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid amide (example B.1) (356 mg, 1.5 mmol) according to general procedure II. Obtained as a yellow solid (90 mg, 18%). MS (ISP) 512.3 [(M+H)+]; mp 239-240° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 84 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (150 mg, 0.35 mmol), 2,2,2-trifluoro-ethylamine (176 mg, 1.77 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 130 mg (84%). LC-MS: 443.0 (MH+, m/z), 2.27 (Rt, min).
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]Cl)=[CH:28][CH:27]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=1.[I-:39].[Na+]>CC(=O)CC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:39][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:2]2([OH:1])[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:9][CH:10]=3)[O:5][CH2:4][CH:3]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=2)=[CH:31][CH:30]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCCl)cc2)cc1
Reactant: [I-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCOCCI)cc2)cc1
Yield: 92 %

Procedure:
4-Hydroxy-4-{4-[2-(2-chloroethoxy)ethoxy]phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman (490 mg, 0.9 mmol) was dissolved in 2-butanone (30 ml) under argon atmosphere. Then, sodium iodide (1.4 g, 9.3 mmol) and tetrabutylammonium iodide (1.6 g, 4.5 mmol) were added thereto, and the mixture was refluxed for 16 hours. The reaction solution was cooled down to normal temperature, concentrated, and diluted with ethyl acetate. Then, in order to eliminate the resulting NaCl and the excess sodium iodide and tetrabutylammonium iodide, the solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (n-hexane:ethyl acetate=4:1→2:1) to give the title compound (527 mg, yield 90%) which is pale yellow and sticky. Mass [M−H2O]+=619 Step 3) Synthesis of 4-hydroxy-4-{4-{2-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]ethoxy}phenyl}-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]chroman
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].Cl[CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22]>>[CH3:5][N:4]1[C:6]2[N:7]=[CH:8][N:9]([CH3:10])[C:11]=2[C:12](=[O:13])[N:1]([CH2:15][CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[C:2]1=[O:3]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.075 mol of theobromine and 0.09 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23 and crystallized from diisopropyl ether.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6]2.FC(F)(F)C(O)=O>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Ic1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: Ic1cccc2c1CNC2

Procedure:
Prepared in analogy to Example A2(c) from 4-Iodo-2-trityl-2,3-dihydro-1H-isoindole and trifluoroacetic acid. Light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:20])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>>[CH:1]1([CH2:4][C:5](=[O:20])/[C:6](/[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:21]\[N:22]([CH3:24])[CH3:23])[CH2:2][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccnc(Nc2ccncc2)n1)CC1CC1
Product: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
1-Cyclopropyl-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]propan-2-one (8) (269 mg, 1.003 mmol) was taken up in DMF-DMA (5.369 mL, 40.1 mmol) and stirred at 80° C. for 30 minutes. The solvent was evaporated and the residue partitioned between DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage™ silica gel chromatography [1-13% MeOH in DCM with 1% triethylamine] to afford the desired product as an orange/brown foam (320 mg, 99% yield). MS (ES+): m/z=324.3 (100) [MH+2]. HPLC: tR=0.88 minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35]Br>CN(C=O)C.C(OCC)(=O)C>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: Fc1ccc(CBr)cc1F
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3.00 g) was added to a suspension of sodium hydride (60%, 340 mg) in DMF (5 mL) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, 3,4-difluorobenzyl bromide (1.53 g) was added under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccccc1)Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
A solution of 4-chloro-2-(bromoacetamido)benzoic acid from Example 40 (6.5 g, 0.02 mol), aniline (5.2 mL, 250 mol %) and anhydrous DMF (50 mL) was heated to 100-105° C. for 4 h, and stirred at rt for 20 h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified with aqueous 5% HBr to pH=3. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Trituration of the resulting solid with diethyl ether afforded 4.5 g (66%) of the crude title compound as light-beige crystals, mp 177.8-180° C. The crude compound (4.5 g) was stirred with EtOAc (~100 mL) and the resulting insoluble portion was filtered off. The filtrate was concentrated to a light-beige solid which was refluxed with benzene (80 mL) for 40 min. The bnenzene mixture was filtered while hot and the filtered solid was dried for 4 h under high vacuum, yielding 2.75 g (40%) of the title compound as light crystals, mp 229-230° C. (became "wet" at 227° C.); 1H NMR (DMSO-d6) δ 13.6 (bs, 1H), 12.11 (s, 1H), 8.82 (d, J=1.6, 1H), 7.93 (d, J=8.8, 1H), 720 (dd, J=6.0, J=2.6, 1H), 7.10 (t, J=7.6, 2H) 6.63-6.58 (m, 4H), 3.85 (s, 2H); 13C NMR (DMSO-d6) δ 171.48, 168.31, 148.01, 141.53, 138.58, 132.86, 128.97, 128.30, 122.61, 118.72, 118.67, 117.16, 114.68, 112.45, 48.89.