Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][OH:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].C(N(CC)CC)C.[S:35](Cl)([CH3:38])(=[O:37])=[O:36]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][O:24][S:35]([CH3:38])(=[O:37])=[O:36])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino) benzyloxy]-2-methylimidazo[1,2-a]pyridine (700 mg) and triethylamine (269 mg) in methylene chloride (14 ml) was added mesyl chloride (224 mg) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give the residue of 3-bromo-8-[2,6-dichloro-3-(N-mesyloxyacetyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine. The residue was dissolved in N,N-dimethylformamide (7 ml) and potassium phthalimide (362 mg) was added thereto at ambient temperature under N2 atmosphere. The mixture was stirred for 1 day, and water was added thereto. The precipitate was collected by filtration and dried to give 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-phthalimidoacetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (629 mg).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH3:32])=[O:30])[CH2:6][C@@H:5]1[OH:33])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[C:34]([O:33][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH3:32])=[O:30])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NCCC(C)C)C[C@]2(C)[C@@H](C(=O)OC)CC[C@@H]32)C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NCCC(C)C)C[C@]2(C)[C@@H](C(=O)OC)CC[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
Methyl 2β-ethoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (464 mg) in chloroform containing dry PTSA (344 mg) was stirred for 20 min, then treated with acetic anhydride (1.0 ml) and the mixture left for 3 h. The reaction mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, washed with dilute ammonia solution (2×), water (1×), dried and evaporated to give an oil. This was purified by preparative t.l.c. in CHCl3 /MeOH (20:1) to give the title compound as an oil (415 mg), [α]D +27.9°, νmax 1725 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1.C[O:33]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([OH:33])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 73.5 %

Procedure:
The procedure of Example 6 was repeated except that 105 mg of 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 80 mg of 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NCCNc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCNc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, N-phenylethylenediamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[C:3]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: Oc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a mixture of 6,7-dichloro-2-cyclohexyl-5-hydroxybenzo[b]thiophene and 110 ml of 2-butanone is added 11.5 g of ethyl bromoacetate in 60 ml of 2-butanone, followed by 10 ml dimethylformamide and 9.5 g of potassium carbonate. The reaction mixture is stirred under nitrogen at 90°-95° for 3 hrs, allowed to cool and filtered. The filtrate is poured into a mixture of 100 ml water and 100 ml ether. The layers are separated and the aqueous layer is extracted with 200 ml of ether. The organic layers are combined dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid which is recrystallized in ether-hexane to give 14.8 g of ethyl [(6,7-dichloro-2-cyclohexylbenzo[b]thien-5-yl)oxy]acetate, mp 73°-75°.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:14])[N:3]=1.O[CH:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C([OH:28])CCC>>[CH3:14][C:4]1[N:3]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:16][CH2:17][OH:28])[CH2:19][CH2:20]2)[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[N:5]=1
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)C(C)O2
Reactant: CCCCO
Reactant: CC(O)N1CCNCC1
Product: Cc1nc2c(c(N3CCN(CCO)CC3)n1)OC(C)C(=O)N2

Procedure:
A mixture containing 0.86 g of 4-chloro-2,6-dimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. Geterotsikl. Soed. 1972, 1285), 20 ml of n-butanol and 1.04 g of 1-hydroxyethylpiperazine is refluxed for 7 hours, then evaporated. After adding 20 ml of water, the residue is extracted with ethyl acetate. The organic solution is dried and evaporated. After recrystallizing the residue from ethyl acetate, 0.90 g of product is obtained, m.p.: 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:10][C:5]2=[C:4]([O:24][CH3:23])[CH:3]=1
Reactant: Clc1cc(Cl)c2ncn(Cc3cccc4ccccc34)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc2ccccc12
Yield: 69.6 %

Procedure:
5,7-Dichloro-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (150 mg, 0.457 mmol) and sodium methoxide (0.157 mL, 0.686 mmol) in Methanol (1.5 mL) were irradiated in a microwave oven for 1 h at 110° C. The mixture was diluted with water, the precipitate was collected, washed with water, dried to give 5-chloro-7-(methyloxy)-3-(1-naphthalenylmethyl)-3H-imidazo[4,5-b]pyridine (143 mg, 0.318 mmol, 69.6% yield) which was used as is in the next step. MS (ES+) m/e 324 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (s, 1H), 8.24 (d, J=7.83 Hz, 1H), 7.95-8.03 (m, 1H), 7.91 (d, J=8.08 Hz, 1H), 7.60 (qd, J=7.20, 5.43 Hz, 2H), 7.44 (dd, J=8.21, 7.20 Hz, 1H), 7.02 (d, J=7.07 Hz, 1H), 6.99 (s, 1H), 5.93 (s, 2H), 4.10 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:31]3[CH2:32][CH2:33][N:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:29][CH2:30]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ncccn4)CC3)C2)cc1OC
Yield: 68.3 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (24.9 mg, 0.092 mmol), 1-(2-pyrimidyl)piperazine dihydrochloride (20.0 mg, 0.084 mmol), molecular sieve (5 beads), NaBH(OAc)3 (53.6 mg, 0.252 mmol) and diisopropylethylamine (53.9 L, 0.168 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.6 mg (68.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][C:16]=1[CH2:15][C@H:14]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:5])[CH3:4]>O1CCCC1>[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][C:16]=1[CH2:15][C@H:14]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:2][CH3:1])(=[O:5])[CH3:4]
Reactant: CN
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCOS(=O)(=O)c4ccc(C)cc4)Cc4cc(OC5CCCCO5)ccc4[C@H]3CC[C@]12C
Solvent: C1CCOC1
Product: CNCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Yield: 79.8 %

Procedure:
6.3 g of methylamine is condensed in a pressure pipe while being cooled with ice in a solution of 8.2 g of 17β-acetoxy-3-(tetrahydropyran-2-yloxy)-7α-(5-p-toluenesulfonyloxypentyl)-estra-1,3,5(10)-triene in 80 ml of tetrahydrofuran. The closed pressure pipe is then heated for 6 hours to 60° C. After cooling, it is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel. 5.1 g of 17β-acetoxy-7α-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene is obtained as oil. [α]D22 =+29.7°(c=0.535% in chloroform)
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.N[C:49]1[N:54]=[CH:53][C:52]([CH2:55][N:56]([CH3:62])[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[CH:51][CH:50]=1>C(Cl)Cl.CO>[CH3:60][N:59]([CH3:61])[CH2:58][CH2:57][N:56]([CH2:55][C:52]1[CH:51]=[CH:50][C:49]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])=[N:54][CH:53]=1)[CH3:62]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][CH:2]=[CH:3][CH:4]=[C:5]([CH3:9])[CH2:6][CH:7]=[O:8].CCCCC.C(N(CC)CC)C.Br[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[Br:1][CH:2]=[CH:3][CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][O:8][Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)Br
Reactant: CC(=CC=CBr)CC=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C=CO[Si](C)(C)C)=CC=CBr
Temperature: 0 °C
Reaction time: 48 h
Yield: 40.6 %

Procedure:
6-Bromo-3-methyl-3,5-hexadienal (0.95 g; 5 mmol) dissolved in acetonitrile (25 cc) and pentane (25 cc) is introduced, under an argon atmosphere, into a 100-cc round flask fitted with a septum and a magnetic stirrer. Triethylamine (1 g; 10 mmol, i.e. 2 equivalents) is then added. After the mixture has been cooled to 0° C., bromotrimethylsilane (1.53 g; 2 equivalents) is added dropwise. The temperature is allowed to return to about 20° C. After 48 hours the reaction is complete. The acetonitrile phase is extracted with pentane (4×15 cc) under an argon atmosphere. After evaporation of the solvent and distillation, 6-bromo-3-methyl-1-trimethylsilyloxy-1,3,5-hexatriene (0.53 g) is obtained (b.p. 0.06 kPa=92°-95° C.). The yield is 46.8%. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: CC1(CNc2nc(F)ccc2F)CCOCC1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCC2(C)CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
To a solution of 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (1.4 g, 5.78 mmol) in MeOH (14 mL) was added sodium methoxide (25 wt. % in MeOH, 7 mL, 30.8 mmol). The mixture was heated in a steel bomb at 135° C. for 3 days. The mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (200 mL), and the resulting precipitate was filtered off and rinsed with water. The solid was dissolved in DCM. The organic solution was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, 20 min, EtOAc/heptane= 0/100 for 2 min, then EtOAc/heptane= 5/95 to 25/75 over 23 min, EtOAc/heptane= 25/75] providing 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as an off-white solid. Yield: 1.22 g. LCMS (m/z): 255.1 [M+H]+; Retention time=0.89 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([OH:14])=[C:11]([C:15]([O-:17])=[O:16])[CH2:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[CH2:13][C:12]([OH:14])=[C:11]([C:15]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:10][C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])C1=C(O)CN(Cc2ccccc2)C(=O)C1
Reactant: OCc1ccccc1
Product: O=C(OCc1ccccc1)C1=C(O)CN(Cc2ccccc2)C(=O)C1
Yield: 81.5 %

Procedure:
A solution of 1-benzyl-5-hydroxy-2-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate 4 (14 g, 50.9 mmol) in benzyl alcohol (27.5 g, 255 mmol) was heated at about 170° C. for about 16 hours. The solvent was removed in vacuo, and the resulting residue was re-crystallized from ether to give the title product as a yellow solid (14 g; yield=85%). LC-MS: m/z=338 (M+H)+.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([O:15][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To an ice-cooled solution of Boc-D-Trp-OH (8.61 g) in DMF (100 ml) were added benzyl bromide (7.19 g) and diisopropylethylamine (4.02 g). The solution was stirred for two hours at the same temperature and overnight at room temperature. After evaporation, the residue was extracted with ethyl acetate. The organic layer was washed successively with water, sodium hydrogencarbonate solution, 0.5 hydrochlolic acid, and sodium chloride solution, and dried over magnesium sulfate. Evaporation gave Boc-D-Trp-OBzl (10.6 g) as a crystalline mass.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:21](Cl)(=[O:29])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:21](=[O:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:1][CH2:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a mixture of 2-hydroxy-4′-trifluoromethyl acetophenone (24.0 g), pyridine (10.3 g) and tetrahydrofuran (200 ml) was added dropwise phenyl chlorocarbonate (20.4 g) under ice-cooling, which was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into water (500 ml), and extracted with ethyl acetate (150 ml×2). The organic layer was washed with water and then a saturated aqueous solution of sodium chloride, which was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to crystallization by addition of isopropyl ether (100 ml) to give crystals of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.9 g, 53%). Melting point 134-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[N:27]([CH3:28])[C:26]([CH3:29])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:22])(=[O:21])[NH:16]C(C)(C)C)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([C:23]2[N:27]([CH3:28])[C:26]([CH3:29])=[N:25][CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:21])(=[O:22])[NH2:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(S(=O)(=O)NC(C)(C)C)cc3)ncc2Cl)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COc1ccccc1
Product: Cc1ncc(-c2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc2Cl)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
A mixture of 5-chloro-4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butyl)sulphamoyl]anilino}pyrimidine (Example 60; 116 mg, 0.267 mmol), trifluoroacetic acid (2.7 ml), water (0.3 ml) and anisole (145 μl, 1.34 mmol) was stirred at ambient temperature for 72 hours. The mixture was then concentrated by evaporation and the residue treated with water and ether. The precipitated solid was collected by filtration, washed with water and ether, and dried to give the title compound (87 mg, 86%) as a white solid. NMR: 2.4 (s, 3H), 3.78 (s, 3H), 7.15 (s, 2H), 7.65 (s, 1H), 7.73 (d, 2H), 7.83 (d, 2H), 8.6 (s, 1H), 10.11 (s, 1H); m/z 3.78 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]([F:25])([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH:13]([F:15])[F:14].[Si](C#N)(C)(C)C.[N:32]1([C:37](N2C=CN=C2)=[O:38])C=CN=[CH:33]1>>[F:11][C:12]([F:25])([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[N:1]([C:2]3[CH:10]=[CH:9][C:5]4[NH:6][CH:7]=[N:8][C:4]=4[CH:3]=3)[C:37](=[O:38])[NH:32][CH2:33]2)=[CH:19][CH:18]=1)[CH:13]([F:15])[F:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(OC(F)(F)C(F)F)cc1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(OC(F)(F)C(F)F)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.888 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.978 mL, 7.0 mmol), di-(imidazol-1-yl)methanone (0.621 g, 3.83 mmol) as described in method 2. The product was purified by means of FPLC.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26](Cl)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]([C:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([N:30]4[N:31]=[CH:32][CH:33]=[N:29]4)=[C:21]3[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(-n3nccn3)ccnc12

Procedure:
Example 205 and 206. In a sealed tube -(4-benzoyl-piperazin-1-yl)-2-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione (30 mg, 0.076 mmol), 1H-1,2,3-triazole (160 mg, 2.3 mmol), Cu (0) (10 mg, 0.16 mmol) and K2CO3 (11 mg, 0.080 mmol) were heated at 160° C. for 16 h. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The residue was purified by preparative HPLC to provide 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d, J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS nz/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.91 min (Column G); and 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) δ 8.97 (d, J=81.2 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47 (br s, 5H), 4.00-3.45 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.90 min (Column G).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24]C2C=CC(C(F)(F)F)=CN=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.Br[C:60]1[CH:61]=[N:62][CH:63]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:65]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:60]2[CH:61]=[N:62][CH:63]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:65]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 31 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 3-bromo-5-(trifluoromethyl)pyridine in 31% yield.