Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.O[CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F-].C[N+](C)(C)C>CN(C=O)C.C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:23][C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=3)[N:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)Nc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(=O)[nH]n2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(O)c3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
17 g (56.2 mmol) of 6-[3-(tert-butyldimethylsilanyloxy)phenyl]-2H-pyridazin-3-one, 11 g (56.2 mmol) of ethyl (3-hydroxymethylphenyl)carbamate and 14.7 g (56 mmol) of triphenylphosphine are dissolved in 100 ml of DMF and 400 ml of THF. Under a nitrogen atmosphere, the yellow solution is cooled to 0° C., and 4.1 ml (26 mmol) of diethyl azodicarboxylate are slowly added dropwise, and the reaction mixture is stirred at room temperature for 20 h. The yellow suspension is evaporated to dryness. Water is added to the residue, which is then extracted with ethyl acetate, dried over sodium sulfate, and the solvent is distilled off. The residue is stirred for 15 h with isopropanol, the resultant precipitate is filtered off with suction and rinsed with isopropanol. The residue is dried in vacuo (6.8 g), 150 ml of THF are added, and 5 g (61 mmol) of tetramethylammonium fluoride are added. The mixture is stirred at room temperature overnight. The reaction mixture is evaporated. The residue is taken up in ethyl acetate, and water is added. A solid precipitates out, which is filtered off with suction and discarded. The organic phase is separated off from the aqueous phase. The organic phase is washed again with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A163) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C(OCC)(=O)C.[OH-].[K+]>C(O)C>[F:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:3]2[CH2:2][O:22]2)[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 0.5 h

Procedure:
tert-Butyl (1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 2) is dissolved in absolute alcohol (150 mL) and ethyl acetate (100 mL) and potassium hydroxide (2.3 g, 34.9 mmole, 1.1 eq.) in ethyl alcohol (85%, 5 mL) is added at −20 degrees C. The cold bath is then removed and the mixture stirred for 0.5 hour. The reaction is monitored by TLC (ethyl acetate/hexane, 20/80). When the reaction is complete, it is diluted with dichloromethane and extracted, washed with water, saline, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The crude material is purified by flash chromatography on silica gel to give the title compound, TLC (ethyl acetate/hexane, 20/80) Rf=0.3; MS (MH+)=300.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=O)[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>CCOCC.CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:17]([CH2:21][CH3:22])[C:18](=[O:20])[CH:40]=[N+:38]=[N-:39])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C#CC(CC)N(C(CC)C(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C#CC(CC)N(C(CC)C(=O)C=[N+]=[N-])S(=O)(=O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound 60 (498 mg, 1.45 mmol) in 7.5 mL of Et2O were added sequentially 0.24 mL of triethylamine (1.2 eq), 0.23 mL of isobutyl chloroformate (1.2 eq) at −30° C. After being stirred at −30° C. for 15 min, diazomethane (prepared by mixing MNNG and KOH in diethyl ether) (excess) was added to the above mixture at 0° C. and stirred there for 5 hours. Glacial HOAc (1.5 mL) was added to destroy the excess diazomethane and the solution was extracted with EtOAc. The organic phase was washed with sat NaHCO3, water, brine and dried (MgSO4). LCMS 368.1 (M+1).
Reaction SMILES: C([O:4][C:5](=[O:69])[C@@H:6]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:7][C:8]1[CH:60]=[CH:59][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:19]([NH:21][C@H:22]([C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])[CH2:23][S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:20])=[O:14])=[CH:10][CH:9]=1)C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:55]([O:54][C:52]([NH:51][C@@H:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:5]([OH:69])=[O:4])=[CH:60][CH:59]=1)=[O:14])[C:19]([NH:21][C@H:22]([C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])[CH2:23][S:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:20])=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NCC(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NCC(N)=O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
60 mg (0.031 mmol) of the compound from example 16A was dissolved in approx. 3 ml tetrahydrofuran. 22 μl (0.16 mmol) Triethylamine, 6 μl (0.16 mmol) formic acid and 4 mg (0.003 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 5 ml water and twice extracted with approx. 5 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 26 mg (86% of theory) product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:31])[N:20]=2)=[O:18])=[C:10]([CH3:32])[N:9]=1)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[N:9]=[C:10]([CH3:32])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:31])[N:20]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)n(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1nc(Cc2ccccc2)n(C)n1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
(5-{[(5-Benzyl-1-methyl-1H-[1,2,4]triazole-3-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (29 mg, 0.064 mmol) was dissolved in a mixture of dichloromethane (4 ml) and TFA (1 ml). The reaction mixture was shaken at 23° C. for 18 h. Solvents were removed in vacuo. The residue was dissolved in dichloromethane/methanol 1:1 (1 ml) and purified over VARIAN SCX-SPE cartridge (strong cation exchange), washing with methanol and releasing the compound with 2M ammonia in methanol. The basic fraction was evaporated in vacuo to give the title compound. 1H-NMR (DMSO, 400 MHz) 8.5 (s, 1H), 7.2-7.3 (m, 5H), 7.0 (br s, 2H) 6.5 (s, 1H), 4.3 (d, 2H), 4.2 (s, 2H), 3.8 (s, 3H), 2.4 (s, 3H), 2.3 (s, 3H). UPLC-MS (method F) Rt=0.92 min, [M+H]+=351.4. HPLC (method G) Rt=1.281 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[C:4]([F:18])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:27])=[O:10])=[C:4]([F:18])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(C(=O)O)c1ccc(Cl)cc1F)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C(C(=O)Cl)c1ccc(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (2.32 mmol) of (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (diastereomer mixture) were dissolved in 2 ml of dichloromethane. After addition of a small drop of DMF, the reaction solution was cooled to from −5° C. to 0° C., and 0.4 ml (4.64 mmol) of oxalyl chloride was added dropwise. Cooling was removed and the reaction mixture was stirred at RT for 1 h until the evolution of gas had ceased. The mixture was then concentrated under reduced pressure. The residue was twice taken up in abs. dichloromethane, in each case reconcentrated under reduced pressure and the residue was finally dried under high vacuum. This gave 640 mg of the target product which was directly, without further purification, reacted further.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[N:13]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])C(=O)[O-])(C)(C)C>ClCCl>[CH3:26][Si:24]([CH3:25])([CH3:27])[CH2:23][CH2:22][C:18]1[S:19][CH:20]=[CH:21][C:17]=1[NH2:13]
Reactant: CC(C)(C)ON(C(=O)[O-])c1ccsc1CC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCc1sccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
5 ml of trifluoroacetic acid are added to a solution consisting of 2.8 g (9.3 mmol) of tert-butoxy[2-(2-trimethylsilanylethyl)thiophen-3-yl]carbamate (IX-1) in 50 ml of dichloromethane. The reaction solution is stirred at room temperature for 3 h and then concentrated under reduced pressure. Column chromatography (gradiant cyclohexane/ethyl acetate 4:1 to 1:1) gives 1.2 g (65% of theory) of 2-(2-trimethylsilanylethyl)thiophen-3-ylamine [log P (pH 2.3)=1.78].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: Cc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2(O)CCNCC2)cc1C(F)(F)F

Procedure:
According to Preparation 2: Tert-butyl 4-[4-methyl-3-(trifluoro-methyl)phenyl]-4-hydroxypiperidine-1-carboxylate (5.5 g, 15.3 mmol, methylen chloride (30 ml), trifluoroacetic acid (4.5 ml). Yield: 1.97 g. MS m/z (rel. intensity, 70 eV) 259 (M+, 14), 241 (84), 240 (43), 187 (19), 56 (bp).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:8]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:7]2[C:6]=1[OH:23])=[O:4].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C[O-].[Na+]>>[Cl:22][C:20]1[CH:21]=[C:7]2[C:6]([OH:23])=[C:5]([C:3]([NH:24][C@@H:25]([CH3:26])[C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:8]2[CH:19]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccccn2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-pyridin-2-ylmethyl-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 391 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3ccccc3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3ccccc3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (100 mg, 0.153 mmol) in dioxane (13 mL) and a 1M aqueous KOH solution (0.764 mL, 0.764 mmol) was heated at 90° C. for 6 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (100 mL), washed with a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain as a yellow solid (56 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 6H), 3.07-3.20 (m, 2H), 3.50 (br s, 2H), 3.76 (s, 3H), 4.13 (d, J=8.24 Hz, 2H), 6.19-6.31 (m, 1H), 6.87-7.05 (m, 3H), 7.31 (t, J=7.87 Hz, 1H), 7.61 (s, 1H), 7.71 (br s, 1H), 7.78 (d, J=7.51 Hz, 1H), 8.26 (br s, 1H), 8.59 (s, 1H), 8.94 (d, J=8.61 Hz, 1H), 11.23 (s, 1H), 12.04 (s, 1H); ESIMS (M+H)+=501.25.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:15][CH:16]=O)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:18]I>>[CH3:1][O:3][CH2:4][CH:5]([N:15]([CH3:16])[CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CNC(CCOc1ccccc1)COC=O
Reactant: CI
Product: COCC(CCOc1ccccc1)N(C)C

Procedure:
2-(formylamino)-4-phenoxy-1-butanol formate, described in Example 3, with methyl iodide, followed by reduction, gives 1-methoxy-N,N-dimethyl-4-phenoxy-2-butanamine,
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)CCC.CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)OC(C)(C)C)nc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C(=O)O)cc2)cn1
Reaction time: 5 h
Yield: 50.1 %

Procedure:
At room temperature, methyl 4-[2-(tert-butoxycarbonylamino)pyridin-5-yl]benzoate (250 mg) was suspended in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), followed by the addition of a 1N aqueous sodium hydroxide solution (8 ml). The resulting mixture was stirred for 5 hours. The reaction mixture was made weakly acidic with an aqueous citric acid solution, followed by the addition of saturated saline and n-butanol to separate the organic layer. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby the title compound (120 mg, 49%) was obtained as a crude purified product.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16].[H-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>CN(C=O)C>[CH3:1][C:2]1[C:15]2[N:14]([CH2:22][CH2:21][CH2:20][Cl:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16]
Reactant: ClCCCI
Reactant: Cc1ccc2c(c1C)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)N(CCCCl)c1ccccc1S2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 5.0 g of 1,2-dimethylphenothiazine in N,N′-dimethylformamide was added 970 mg of sodium hydride under stirring at room temperature. After stirring at room temperature for 30 min, 4.0 g of 1-chloro-3-iodopropane was added dropwise followed by stirring at room temperature overnight. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 3.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:9]2[O:8][C:4]3[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Oc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=c1c2ccc(F)cc2oc2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
700 grams of 2-(3-fluorophenyloxy)-5-trifluormethylbenzoic acid were dissolved in 3000 milliliters of concentrated sulfuric acid whereby the temperature rose to 60° C. The mixture was stirred at 45°-50° C for one hour and then poured onto 10 liters of crushed ice. The precipitate was filtered off, suspended in 1000 milliliters of acetone, made alkaline with concentrated aqueous ammonia and reprecipitated with ice and water to a volume of 10 liters. The precipitate was filtered, washed with water and dried in vacuum; whereupon it was recrystallized to yield 167 grams of 2-trifluoromethyl-6-fluoroxanthen-9-one which melts at 140°-142° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([C:10]3[C:11]([NH:16][C:17]4[C:18]5[CH:19]=[CH:20][N:21]=[C:22](Cl)[C:23]=5[CH:24]=[CH:25][C:26]=4[CH3:27])=[N:12][CH:13]=[CH:14][CH:15]=3)=[C:4]2[CH:3]=[N:2]1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCN(CC)CC.CC(O)=O.C(Cl)Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([C:10]3[C:11]([NH:16][C:17]4[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]5[C:18]=4[CH:19]=[CH:20][N:21]=[C:22]5[NH:29][C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)=[N:12][CH:13]=[CH:14][CH:15]=3)=[C:4]2[CH:3]=[N:2]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of N-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine (160 mg, 413 mmol), 4-aminobenzonitrile (53.6 mg, 454 μmol), tris(dibenzylideneacetone)dipalladium(0) (18.9 mg, 20.6 μmol) and DavePhos (17.9 mg, 45.4 mmol) in THF (3 ml) was slightly vacuumed to de-gas, and then lithium bis(trimethylsilyl)amide (1.0 M solution in THF) (1857 μl, 1857 μmol) was added and the microwave tube was sealed under N2 gas. The mixture was heated in a microwave reactor at 100° C. for 30 min. The mixture was poured into DCM (10 ml)-AcOH (0.5 ml) and stirred for 10 min, then Et3N (0.5 ml) was added. Solvent was removed under vacuum and the residue was purified by flash chromatography eluting with MeOH/DCM (1-4%) to give 4-(5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile. MS Found: (ESI pos. ion) m/z 470 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])(=O)=O.O>CC#N.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC1(C)CCn2c(nc(Cl)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)OCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Temperature: 65 °C
Yield: 67.7 %

Procedure:
0.2 g of 2-chloro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are suspended in 7 mL of CH3CN, 0.61 g of cesium carbonate and 0.34 g of 2-isopropoxyethyl methanesulfonate are added. The mixture is heated to 65° C. for 72 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel SiO2 (CH2Cl2/MeOH, 99/1). 0.19 g (yield=67%) of 2-chloro-9-(2-isopropoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][OH:20]>>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][O:20][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: OCc1ccco1
Reactant: Clc1cncc(N2CCNCC2)n1
Product: c1coc(COc2cncc(N3CCNCC3)n2)c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
K-t-BuO (1.55 g, 13.8 mmol) was added to a mixture of the product from step 2 above (1.40 g, 7.05 mmol) and 2-furanmethanol (5.3 g, 54 mmol). After being stirred for 7.5 h at 110° C., the mixture was applied onto a bed of silica (16×6 cm). Elution with CHCl3/MeOH (95:5 followed by 90:10) fumished 1.35 g (74%) of the title compound as an oil. HRMS m/z calcd for C13H16N4O2 (M)+ 260.1273, found 260.1276. Anal. (C13H16N4O2) C, H, N.