Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[I:10]N1C(=O)CCC1=O>C(O)(=O)C>[I:10][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccnc(N)n1
Solvent: CC(=O)O
Product: COc1nc(N)ncc1I
Temperature: 80 °C

Procedure:
To a solution of 4-methoxy-pyrimidin-2-ylamine (405 mg) in acetic acid (10 mL) was added N-iodosuccinimide (950 mg) and the mixture was heated at 80° C. for 4 h. After cooling to room temperature, the reaction was quenched with 5% aqueous sodium thiosulphate solution (20 mL) and the solvent removed in vacuo. The product was then extracted into dicholoromethane (3×20 mL) and the combined organics were washed with brine (40 mL), dried (MgSO4) and reduced in vacuo to give 5-iodo-4-methoxy-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[CH3:17]O>>[CH3:17][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1cccc(Br)n1
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)n1
Temperature: 0 °C

Procedure:
6-Bromopyridine-2-carboxylic acid (6.000 g) was heated in refluxing methanol (180 mL) containing conc. sulphuric acid (2 mL) for 4 hrs. The reaction mixture was then cooled to ˜0° C. and conc. ammonia (4.8 mL) was added. The resulting solution was evaporated to give a white residue. This white solid was partitioned between brine and dichloromethane (100/100 mL). After thorough shaking the organic layer was dried (magnesium sulphate) and evaporated to give a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][N:13]([CH2:14][CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1OCCN(C)C
Yield: 20.5 %

Procedure:
Acetonitrile (30 mL) solution of 2 g of 2-methyl-4-nitrophenol, 1.87 g of 2-dimethylaminoethyl chloride and 5.4 g of potassium carbonate was stirred at 120° C. for 23 hours. The reaction liquid was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the crude product was purified through silica gel column chromatography (chloroform/methanol) to obtain 600 mg of the entitled compound as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[CH2:31][O:22][C:15]1[CH:14]=[C:13]2[C:18]([N:19]=[CH:20][CH:21]=[C:12]2[C@H:11]([OH:23])[C@@H:10]2[N:5]3[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]3)[CH2:9]2)=[CH:17][CH:16]=1)#[N:36]
Reactant: N#Cc1cccc(CBr)c1
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCc3cccc(C#N)c3)cc12
Yield: 79.1 %

Procedure:
To a solution of 0.6 g (1.91 mmol) of 6-hydroxycinchonine in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 8 ml of anhydrous dimethylformamide is added 0.516 g (2.87 mmol) of anhydrous potassium carbonate followed by 0.329 g (1.91 mmol) of 3-(bromomethyl)benzonitrile (Lancaster) and 4 mg of 18-crown-6. The reaction mixture is heated to reflux for 18 h, cooled and filtered. The filtrate is concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer is washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried with anhydrous magnesium sulphate to yield 0.647 g (1.51 mmol, 79%) of (9S)-6'-(3-cyanobenzyloxy) cinchonane-9-ol as pale off-white solids.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]4[OH:28])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>N1C=CC=CC=1>[C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:27][CH2:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]4[O:28][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccccc3C1O)CC2
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)OC1c2ccccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1-Phenyl-8-[(1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one (0.15 mole) is dissolved in 50 ml of dry pyridine and treated with 3.0 g of n-decanoyl chloride. The resulting solution is stirred under a nitrogen atmosphere for 16 hours. The mixture is then poured into 400 ml of ice-water and the resulting suspension is stirred for 1 hour. Extraction with methylene chloride followed by washing the organic extracts with saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, and concentration in vacuo yields the title compound.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:10]([O:11][CH2:12][O:13][CH3:14])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][C@H:10]([O:11][CH2:12][O:13][CH3:14])[C@H:5]([CH2:3][OH:2])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COCO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a stirred solution of (±)-cis-4-methoxymethoxy-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (1.98 mmol, 0.5 g) in ether (5 mL) at 0° C. was added LAH powder (50 mg) in one lot and continued stirring at 0° C. for additional 20 min followed 10 min at room temperature. TLC analysis of an aliquot of the reaction mixture showed complete consumption of starting material. The reaction mixture was diluted with ether (5 mL), cooled to 0° C., added ethyl acetate drop-wise followed by saturated sodium sulfate. The organic layer was separated, dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes to provide (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.506 g, 93%) as an oil. To a stirred suspension of sodium hydride (4.16 mmol, 0.1 g) in THF (8 mL) at room temperature was added (±)-cis-3-hydroxymethyl-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.84 mmol, 0.506 g) followed 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 1.74 mmol, 0.6 g). The resultant reaction mixture was kept stirring at 50-60° C. for 2 h. The reaction mixture was cooled to room temperature and excess NaH was decomposed by addition of methanol drop-wise. This was diluted with ethyl acetate (20 mL), washed with water (5 mL), separated the organic layer, dried, filtered and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography by eluting with 40% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.93 g, 82% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:11][C@H:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH3:10])=[CH:40][CH:41]=2
Reactant: C[C@H](N)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(F)(F)F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>C(O)(C(F)(F)F)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[CH2:35][CH2:36]3)=[CH:29][CH:30]=2)[N:10]=1
Reactant: COC(=O)Cc1ccccc1CCc1ccnc(S(C)(=O)=O)n1
Reactant: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
A solution of methyl 2-(2-(2-(2-(methylsulfonyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A3) (150 mg, 449 μmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (K2) (168 mg, 538 μmol) in TFE (5 mL) containing TFA (180 μL) was heated at 100° C. under microwave irradiation for 60 minutes. Additional TFA (200 μL) was added and the resulting solution heated at 120° C. under microwave irradiation for a further 40 minutes. Additional TFA (200 μL) was again added and the mixture was heated at 150° C. under microwave irradiation for a further 20 minutes. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A4 as a brown oil (76 mg, 30%). LCMS-A: rt 6.212 min; m/z 566.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:6][N:7]2[C:12]=1[C:11](SC)=[N:10][CH:9]=[N:8]2)([CH3:3])[CH3:2].C([Si](C(C)C)(C(C)C)[N:24]1[C:28]2=[N:29][CH:30]=[C:31]([NH2:33])[CH:32]=[C:27]2[CH:26]=[CH:25]1)(C)C.ClC1C=CC=C(C(OO)=O)C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)(Cl)Cl.C1COCC1>[CH:1]([C:4]1[C:5]([O:15][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:6][N:7]2[C:12]=1[C:11]([NH:33][C:31]1[CH:32]=[C:27]3[CH:26]=[CH:25][NH:24][C:28]3=[N:29][CH:30]=1)=[N:10][CH:9]=[N:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Reactant: CSc1ncnn2cc(OCC(C)O)c(C(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(O)COc1cn2ncnc(Nc3cnc4[nH]ccc4c3)c2c1C(C)C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 0.9 %

Procedure:
1-(5-Isopropyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (262 mg, 0.93 mmol, obtained from Example 25 using procedure in Step B of Example 7) and 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (290 mg, 0.93 mmol) were dissolved in chloroform and m-chloroperbenzoic acid (60%, 535 mg, 1.86 mmol) was added. The mixture was heated at 120° C. for 10 min in a Personal Chemistry Smith Enrys Optimizer™ microwave oven. The solution was evaporated in vacuo and the residue was purified by preparative HPLC. The isolated product was dissolved in of THF (10 mL) and TBAF (1.0 M, 0.2 mL, 0.2 mmol) was added. The mixture was stirred for 5 min. and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound (3 mg, 1%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH2:17][P:18]([O:24]C(C)C)([O:20]C(C)C)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C[Si](C)(C)Br.C(O)C.C1OC1C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH2:17][P:18]([OH:20])([OH:24])=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C=C(COCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(COCc1ccccc1)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of dichloromethane, and 0.8 ml (6 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 6 hours, 10 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation, the residue is dissolved in 5 ml of ethanol, and a mixture of ml of propylene oxide and 5 ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 218°-220° (decomp.).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([NH2:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:25](OC)(OC)(OC)[CH3:26].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:22]([C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:24]=[C:25]2[CH3:26])=[CH:21][CH:20]=1)[CH3:23]
Reactant: COC(C)(OC)OC
Reactant: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1ccc(-n2c(C)nc3ccc(O)nc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Benzyloxy)-N2-(4-ethylphenyl)pyridine-2,3-diamine (358 mg, 1.12 mmol) was dissolved in THF (1.0 mL). Trimethyl orthoacetate (1.0 mL) was added followed by TFA (10 μL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The benzyl group was then removed as described in Example 1.98, Step B to give the title compound as a white solid (55.3 mg). LCMS m/z=254.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnn2)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4cccnn4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-3-yl)phenylboronic acid (50 mg, 0.23 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (56 mg, 0.22 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) gave the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.72 (6H, s), 7.37 (1H, dd, J 11, 9 Hz), 7.60 (1H, dd, J 9, 5 Hz), 8.04 (1H, dt, J 9, 2 Hz), 8.14-8.19 (1H, m), 8.31 (1H, s), 8.82 (1H, s), 8.90 (1H, dd, J 7, 2 Hz), 9.22 (1H, dd, J 5, 2 Hz); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>CO>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:22]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Methyl α-bromo-α-[p-(phenoxy)phenyl]acetate (6.42 g) is reacted with 3.61 g of 4-chlorothiophenol in methanol as in Example 16 to afford a yellow oil which solidifies on standing. Recrystallization from 50 ml of petroleum ether affords the product as white crystals, mp 66°-67.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>CCCCCCC.C(O)C.CC(O)C>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(N)c1cccnn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CC(C)O
Solvent: CCO
Solvent: CCCCCCC
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 47 b), using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (+)-enantiomer was isolated. MS (EI): m/e=432.5 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:33]#N.[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][N:22]([CH3:33])[CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(c2nnc(C(=C3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.029 g, 0.074 mmol) in MeOH (5 mL) was added formaldehyde (0.322 mL, 57% solution in H2O) dropwise at rt. A solution of NaCNBH3 (0.026 g, 0.415 mmol) in MeOH (0.3 mL) was then added and the solution was stirred at rt for 15 min. The resulting mixture was poured into H2O and extracted with EtOAc (×3), and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (NH4OAc) to afford the title compound (0.012 g, 17%) as a colorless solid:
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5](Cl)=[O:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:6]
Reactant: OCC(F)(F)F
Reactant: COC(F)(F)C(F)(F)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(F)(F)C(F)(F)C(=O)OCC(F)(F)F
Reaction time: 8 h

Procedure:
Trifluoroethyl 3-methoxytetrafluoropropionate was prepared by reaction of 97.3 g (0.50 mol) of 3-methoxytetrafluoropropionyl chloride, 55.0 g (0.55 mol) of trifluoroethanol, and 39.5 g (0.50 mol) of pyridine in 100 mL methylene chloride. Reaction was extremely slow until the pyridine was added. After having stirred overnight, the reaction mixture was filtered, solids were rinsed with methylene chloride, and filtrates were distilled to give 119.4 g of ester, bp 44°-49° (20 mm, 2.7 kPa). The cloudy product was treated with 2 g of P2O5 and filtered to afford 109.3 g (93%) of the desired ester, pure by GC. IR (CCl4): 2855, 2975, and 3010 (sat'd CH), 1790 (C=O), and 1300-1100 cm-1 (CF, C--O).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(C(N2CCC(OC3C=CC(NC4C5C=C(F)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[CH3:33][C:32]([CH3:35])([CH3:34])[CH2:36][C:37]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[C:17]4[CH:25]=[C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[N:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:3][C:2]=2[CH3:1])[CH2:10][CH2:11]1)=[O:38]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Agent: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCN(C(=O)CC(C)(C)C)CC1

Procedure:
The title compound was prepared from [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine and tert-butylacetyl chloride by a procedure analogous to the synthesis of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-y}-methanone above.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:19][NH2:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]3)[C:6]=2[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>CCO>[NH2:1][C:2]1[N:3]=[C:4]([S:19]([NH2:20])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]3)[C:6]=2[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1nc(N)nc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ccn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
2-Amino-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolo[2,3-d1pyrimidine-4-sulfenamide 38 (300 mg, 1 mmol) was suspended in EtOH (120 mL) and cooled to 0° C. m-Chloroperoxybenzoic acid (85%, 100 mg, 1 mmol) in EtOH (30 mL) was added dropwise during 1.5 h. After stirring for an additional 30 min at 0° C., the mixture was concentrated to 10 mL in vacuo below 25° C. Ethyl ether (100 mL) was added to the concentrate solution and allowed to stand in the refrigerator overnight. The precipitate was collected by filtration, washed with ethyl ether and dried at 25° C. under reduced pressure to yield 110 mg (35%) of desired compound 39: m.p. 122 C (dec): UV: λmax (pH 1) 352 nm (ε3,100): 272 (3,100), 240 (21,100): λmax (pH 7 ) 336 nm (ε4,800), 239 (21,500): λmax (pH 11) 337 nm (ε4,600), 239 (20,500): IR (KBr) 1060 (S=O) cm-1 :1H NMR (DMSO-d6): δ6.45 (s, 2, exchangeable in D2O, SONH2), 6.49, (dd, 1, J =8.3 and 5.9 Hz, C1'H), 6.62 (s, 2, exchangeable in D2O, NH2), 6.73 (d, 1, J 3.8 Hz, C5H), 7.38 (d, 1, J =3.8 Hz, C6H). Anal. Calcd for C11H15N5O4S: C, 42.16: H, 4.82: N, 22.35: S, 10.23. Found: C, 41.91: H, 4.86: N, 22.07: S, 9.91.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(=O)CC>[C:1]1([O:11][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1cccc2c1CCCC2

Procedure:
10 g 5,6,7,8-tetrahyro-1-naphthol are dissolved in 150 ml 2-butanone and then 18.5 g potassium carbonate and 12.3 g methyl bromoacetate are introduced into the mixture. After having been refluxed for 24 hours, the mixture is filtered, the solvent evaporated under reduced pressure and after removal of the starting phenol soluble in aqueous basic medium, 13.1 g of final product are distilled.