Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(NC(C)C)(C)C.[Li].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]>C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:8])=[CH:5][CH:6]=1)[OH:21]
Reactant: Clc1cccc(Cl)n1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
2,6-dichloropyridine (10.0 g, 67.6 mmol) was dissolved in 220 mL of dry THF and the reaction mixture was cooled to −78° C. under argon. Lithium diisopropylamine (60 mL, 118 mmol, 2M in heptanes) was added to the reaction mixture over 12 minutes via cannula, and the reaction mixture was stirred for 15 minutes at −78° C. 2-Chlorobenzaldehyde (16 mL, 141.96 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by addition of 80 mL saturated ammonium chloride and 200 mL of water, and the aqueous mixture was extracted once with 300 mL of EtOAc and a second time with 250 mL of EtOAc. The comnbined organic phase was washed with saturated brine and water and was dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by FLASH column chromatography using 5%-20% EtOAc/Hexanes to yield 12.2 g of (2-chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanol as a yellow oil. Mass Spec. M+H=290.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=1.[CH2:20](OC(OCC)OCC)C>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[CH:20][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)=[O:19]
Reactant: COC(=O)c1ccc(N)c(NCCN2CCCC2)c1
Reactant: CCOC(OCC)OCC
Product: COC(=O)c1ccc2ncn(CCN3CCCC3)c2c1

Procedure:
4-Amino-3-(2-pyrrolidin-1-yl-ethylamino)-benzoic acid methyl ester (xii) (1.14 g, 4.33 mmol) and triethylorthoformate (20 mL, 120 mmol) were heated at 120° C. for 18 h before being evaporated to dryness. The residue was taken in EtOAc and aqueous saturated NaHCO3. The aqueous layer was extracted 2 times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a brown oil (tR 1.83 min (conditions 8), MH+=274).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C1COCC1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOC(C)=O>[F:14][C:9]([F:15])([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)C(F)(F)Oc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4-(perfluoroethoxy)benzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled in an ice bath for 10 min. A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min. The ice bath was removed after 1 hour, and the reaction was warmed to room temperature and stirred overnight. GC/MS showed the presence of starting material. The reaction was cooled in an ice bath and 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room temperature for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −86.05, −87.84; ESIMS m/z 284 ([M+11]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (1.38 g, 7.41 mmol) in acetonitrile (10 mL) was stirred with triethylamine (2.07 mL, 14.8 mmol) and methyl 2-bromoacetate (1.02 mL, 11.1 mmol) at room temperature for 4 hours and then filtered. The filtrate was concentrated, and after addition of saturated aqueous ammonium chloride, extracted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49]O)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49][CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 95.2 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65 mmol) obtained in Example 5 and t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (950 mg, 2.14 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (600 mg, 2.49 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 9 hours. After the reaction mixture was allowed to cool down, t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (500 mg, 1.13 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) were added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (1.14 g, 1.57 mmol, 95%) was obtained as a pale yellowish browh foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8](C(C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1.[BrH:28]>C(O)(=O)C>[BrH:28].[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Agent: Br
Solvent: CC(=O)O
Product: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7-(tert-butyl)pyrrolo[2,3-d]-pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (55 ml of a 48% solution) was boiled under reflux for 18 hours under nitrogen. The mixture was allowed to cool and a solid was collected by filtration. This solid was washed with methanol and then with ether to give 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidine hydrobromide, m.p. 288-292° C. The hydrobromide salt was converted into the free base by warming with dilute sodium hydroxide solution (100 ml of 5% w/v solution) and ethanol (60 ml) with stirring and removing the ethanol by distillation. The mixture was cooled and the solid was collected by filtration and washed well with water to give 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[NH:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].Cl>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([S:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)(=[O:36])=[O:35])[CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CNC(c2ccc(Cl)c(Cl)c2)O1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CCO[Si](C)(C)C(C)(C)C)OC2c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
1.00 g (2.72 mmole) of 2-[(5R)-(3,4-dichlorophenyl)oxazolidin-5-yl]ethanol t-butyldimethylsilyl ether [prepared as described in the first part of Example 1(f)] was dissolved in 10 ml of pyridine, and 773 mg (3.27 mmole) of 3,4-dimethoxybenzenesulfonyl chloride were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 2 hours under a nitrogen atmosphere. At the end of this time, the reaction mixture was poured into 100 ml of ice-cooled 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 10:1 to 2:1 by volume as the eluent, to give 1.27 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:22]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1csc(-c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Yield: 64 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl bromopyruvate (0.36 mL) and N,N-dimethylacetamide (14 ml) was stirred at 100° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (403 mg, yield 64%) as pale-brown crystals. MS:462 (MH+).
Reaction SMILES: Br.[Cl:2][C:3]1[N:8]=[N:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:10][CH2:9][C:6]2[N:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH:17]=1
Reactant: NCc1ccc(Cl)nn1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A solution of compound 10C (1.00 g, 4.46 mmol) and 4-bromo-2-fluoro-1-nitro-benzene (10D) (0.97 g, 4.40 mmol) in DMF (50 mL) with DIEA (1.30 g, 10 mmol) was stirred at 65° C. for two hours. The reaction was poured into ice/water and the solid precipitate was collected by filtration, washed with water and dried in vacuum over P2O5 overnight to give 1.5 g of desired product (10E). ESI-MS:m/z 342.9 (M+H)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@H:68]([C:88](OCC#N)=[O:89])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]1[CH2:80][S:79][CH2:78][N:77]1[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[O:75])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[NH2:58][C:55]1[CH:56]=[CH:57][N:52]([C@@H:26]2[O:25][C@H:24]([CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]3[C@@H:39]([O:40][C:88](=[O:89])[C@@H:68]([NH:67][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:66])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]4[CH2:80][S:79][CH2:78][N:77]4[C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])=[O:75])[C@@H:38]([OH:41])[C@H:37]([N:42]4[CH:50]=[N:49][C:48]5[C:43]4=[N:44][CH:45]=[N:46][C:47]=5[NH2:51])[O:36]3)([OH:32])=[O:31])[CH2:27]2)[C:53](=[O:59])[N:54]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (50 mg, 0.079 mmol) in water (0.5 mL) and a solution of (R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk83) (118 mg, 0.236 mmol) in tetrahydrofuran (0.5 mL) were added to buffer A (40 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (water/acetonitrile solution) to afford a crude purified product of (4R)-tert-butyl 4-(((5S)-6-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)oxy)-5-((tert-butoxycarbonyl)amino)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk84) (80 mg).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)C=[CH:7][CH:8]=1.CO.C(O)(=[O:21])C>C(OCC)(=O)C>[CH:13]1[C:14]2[C:9](=[CH:5][CH:4]=[C:3]([CH2:8][CH:7]=[O:21])[CH:2]=2)[CH:10]=[CH:11][N:12]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=CCc1ccc2ccncc2c1
Temperature: 2.5 °C

Procedure:
1.75 g (0.0077 mol) of 4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine, 30 ml of methanol, 1.15 ml of glacial acetic acid and 0.73 g of anhydrous ethyl acetate are mixed. The mixture is cooled to 0-5° C. and 1.14 g of 7-isoquinolylacetaldehyde (as obtained according to the Preparation) and, with care, 1.1 g (0.0175 mol) of sodium cyanoborohydride are added thereto. The mixture is stirred at 0-5° C. for 1.5 hours and subsequently at ambient temperature overnight. 7 ml of concentrated hydrochloric acid are added, the mixture is stirred for 10 minutes, the solvent is evaporated under reduced pressure and the residue is taken up in an ethyl acetate/dilute NH4OH mixture. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated. The residue is purified on a column of silica gel, elution being carried out with an ethyl acetate/methanol=9/1 mixture. The title compound is obtained. The dihydrochloride is prepared using a solution of isopropanol saturated with hydrochloric acid. 1.1 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[CH3:11])[C:5](Cl)=[O:6].[N+:16](=[CH2:18])=[N-:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:18]=[N+:16]=[N-:17])[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[CH3:11]
Reactant: C=[N+]=[N-]
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1S(N)(=O)=O
Product: Cc1c(Cl)cc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O

Procedure:
26.7 g of 3-chloro-4-methyl-5-sulfamoyl-benzoyl chloride were reacted in a manner analogous to that described in Example 1 b with diazomethane to yield the 3'-chloro-4'-methyl-5'-sulfamoyl-diazoacetophenone, M.p. 184° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:14](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:14](/[CH:18]=[CH:19]\[C:20]([N:29]3[CH2:30][C:27]([F:31])([F:26])[CH2:28]3)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:4]=[C:3]([C:2]([F:23])([F:1])[F:24])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: O=C(O)/C=C\n1cccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
A 100 mL 3-neck round-bottomed flask was charged with a solution of (Z)-3-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)acrylic acid (0.15 g, 0.429 mmol) in DCM (10 mL) and cooled to 0° C. and 3,3-difluoroazetidine hydrochloride (0.052 g, 0.558 mmol) was added dropwise. T3P (50% in EtOAc) (0.163 g, 0.514 mmol) was added dropwise followed by DIPEA (0.11 g, 0.858 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated under reduced pressure to afford 0.2 g of crude product which was purified by column chromatography (60/120 silica gel, 0-3% ethylacetate:n-hexane gradient) to afford 0.01 g of (Z)-3-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrol-1-yl)-1-(3,3-difluoro azetidin-1-yl)prop-2-en-1-one (Yield 6.6%). 1H NMR (400 MHz, CDCl3, ppm) δ=4.307-4.425 (m, 4H); 5.523-5.443 (d, J=10 Hz, 1H); 6.387-6.404 (t, 1H); 6.500-6.509 (t, 1H); 6.765-6.790 (d, J=10 Hz, 1H); 7.704-7.715 (t, 1H); 7.811-7.845 (m, 3H). LCMS calcd for: C18H13F8N2O [M+H]+435.29. found 425.49 (retention time 3.292 min).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[K].[C:6]([NH:11][C:12](=[S:16])[O:13][CH2:14][CH3:15])(OCC)=[O:7].C(N(CC)CC)C>CO>[C:3]([C:2]1[S:16][C:12]([O:13][CH2:14][CH3:15])=[N:11][C:6]=1[OH:7])#[N:4]
Reactant: CCOC(=O)NC(=S)OCC
Reactant: N#CCCl
Agent: [K]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1nc(O)c(C#N)s1
Reaction time: 2 h

Procedure:
22.8 g of chloroacetonitrile were added dropwise with stirring at room temperature to a suspension of 61.5 g of the potassium salt of ethyl N-carbethoxy-thiocarbamate [described by Guha et al, Indian Chem. Soc., Vol. 6 (1929), p. 570] in one liter of methanol and after stirring the mixture for 2 hours, 30 g of triethylamine were added thereto. The mixture was stirred for another 48 hours and was then refluxed for 2 hours and filtered. The filtrate was concentrated to dryness and the residue was added to sodium hydroxide solution. The resulting solution was washed with ethyl ether, acidified with hydrochloric acid and extracted with ethyl ether. The extracts were dried and evaporated to dryness and the residue was crystallized from petroleum ether to obtain 26.4 g of 5-cyano-4-hydroxy-2-ethoxy-thiazole melting at 132°C.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([NH:13][C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(CC(O)=O)C=CC=CC=1>>[C:7]1([CH2:2][C:1]([N:9]2[CH2:12][CH:11]([NH:13][C:14]3[CH:23]=[CH:22][N:21]=[C:20]4[C:15]=3[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18](=[O:24])[NH:19]4)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:29]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(c1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Product: O=C(Cc1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 360 using the amine intermediate from example 366 and phenylacetic acid to provide 368. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [BH4-].[Na+].CO.[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH3:27])([CH3:26])[N:10]=[C:11]2[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>O>[F:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]([OH:28])[C:9]([CH3:26])([CH3:27])[N:10]=[C:11]2[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.6 %

Procedure:
Sodium borohydride (103 mg) was added to a methanol (8 mL) solution of 3-(5-fluoro-4-keto-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (300 mg, 0.9 mmol) followed by stirring for 2.5 hours at room temperature, pouring water, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 215 mg (yield 74%) of the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:24]([NH2:25])=[N:23][NH:22][C:19]2=[N:20][CH:21]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O>[Cl:8][C:6]1[N:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:25][C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([F:15])[CH:17]=3)[NH:22][N:23]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(C2CCCCC2)n1
Reactant: Nc1n[nH]c2ncc(F)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cnc2[nH]nc(Nc3cc(Cl)nc(C4CCCCC4)n3)c2c1
Temperature: -60 °C
Yield: 50 %

Procedure:
A mixture cooled to −60° C. containing 4,6-dichloro-2-cyclohexylpyrimidine (505 mg, 2.19 mmol), 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (400 mg, 2.63 mmol) and THF (20 mL) was treated drop wise with a 1M solution of lithium bis(trimethylsilyl)amide in THF (5.46 mL, 5.46 mmol). The reaction mixture was then allowed to warm to 0° C. over 1 h before water was added. The reaction mixture partitioned between water and EtOAc, washed with sat. NaCl solution and dried (Na2SO4) and concentrated in-vacuo. The resulting residue was purified by column chromatography (eluting with MeOH/DCM, 5/95) to give the title compound as a solid (380 mg, 50%). MS (ES+) m/e=347. 1H NMR: (DMSO) 1.10-1.96 (10H, m), 2.56-2.69 (1H, m), 7.65 (1H, brs), 8.27-8.39 (1H, m), 8.58 (1H, s), 10.72 (1H, s), 13.34 (1H, s).