Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:48])[F:47])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH2:38][N:39]4[CH2:44]COC[CH2:40]4)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.CN(C)CCO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:45][CH:46]([F:47])[F:48])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH2:37][CH2:38][N:39]([CH3:44])[CH3:40])=[O:35])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC(=O)N2CCC(C(=O)OCCN3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: CN(C)CCO
Product: CN(C)CCOC(=O)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
Using synthetic method analoguous to that of 2-(morpholin-4-yl)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate, the title compound was prepared from 2-(dimethylamino)ethan-1-ol. LCMS (Method 24) [M+H]+=645.2, RT=2.97 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.21 (t, J=73.1 Hz, 1H) 5.30-5.14 (m, 2H), 4.21-4.10 (m, 3H), 3.89-3.78 (m, 1H), 3.24-3.14 (m, 1H), 2.89-2.60 (m, 2H), 2.49-2.45 (m, 2H), 2.16 (s, 6H), 1.89-1.81 (m, 2H), 1.68-1.37 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=[O:2].OS(O)(=O)=O.[CH3:18]O>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([O:8][CH3:18])=[O:7])=[O:2]
Reactant: O=Cc1cc(C(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 84 %

Procedure:
A suspension of 3-formyl-4-hydroxybenzoic acid (3.9 g, 23.5 mmol) in of methanol (50 ml) was cooled below 0° C. To the suspension was added concentrated H2SO4 (3 ml) and the reaction was allowed to warm to ambient temperature and stirred for 60 hours. The reaction was heated to reflux for 12 hours, the solvent evaporated and residue subjected to chromatography (eluant: ethyl ether/hexane) to give methyl 3-formyl-4-hydroxybenzoate as a white solid (3.55 g, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[C:22]#[C:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH3:18])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Cl-].[Na+].[Au+3].[Cl-].[Cl-].[Cl-]>[CH2:1]([O:8][C:9]([N:11]1[C:12]2[C:21](=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC#Cc1ccc(C(=O)OC)cc1NC(=O)OCc1ccccc1
Agent: [Au+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc2ccc(C(=O)OC)cc2n1C(=O)OCc1ccccc1
Yield: 89.8 %

Procedure:
To a solution of methyl 3-benzyloxycarbonylamino-4-(1-pentynyl)benzoate (949 mg) in tetrahydrofuran (24 ml) was added gold(III)sodium chloride (24 mg) under argon atmosphere, and the mixture was heated under reflux for 100 minutes. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of hexane, dichloromethane, and ethyl acetate (6:3:2) to give methyl 1-benzyloxycarbonyl-2-propylindole-6-carboxylate (852 mg) as colorless crystals.
Reaction SMILES: O.NN.[C:4]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][N:10]1C(=O)C2=CC=CC=[C:12]2[C:11]1=[O:20])#[N:5].Cl>CO.O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][NH:10][C:11](=[O:20])[CH3:12])#[N:5]
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCc1cccc(C#N)c1
Yield: 66 %

Procedure:
A solution of hydrazine hydrate (4.0 g) in methanol was added dropwise to a mixture of N-(3-cyanobenzyl)phthalimide (17.0 g) in tetrahydrofuran (150 ml) and methanol (120 ml) at ambient temperature under stirring and the resultant mixture was stirred for 3 hours at ambient temperature. To the reaction mixture was added dropwise 6N-hydrochloric acid (25 ml) and the mixture was stirred for one hour at ambient temperature. The reaction mixture was evaporated in vacuo. To the residue was added water (60 ml) and the mixture was stirred at 10 minutes and filtrated. The filtrate was washed with ethyl acetate and adjusted to pH 8.0 with 20% potassium carbonate solution. Acetic anhydride (15 ml) was added dropwise to the resulting solution at 8° to 20° C. under stirring and the mixture was stirred for one hour at 10° to 20° C. The reaction mixture was extracted with ethyl acetate, and extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give N-(3-cyanobenzyl)acetamide (7.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH3:13].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[C:16]([F:21])[CH:17]=2)=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
5-bromo-2-chloro-benzoyl chloride 2a (12.4 g, 48.8 mmol) and 1-ethoxy-2-fluoro-benzene 4b (6.84 g, 48.8 mmol) were dissolved in 100 mL dichloromethane and cooled to 0° C., followed by addition of aluminum trichloride (5.86 g, 44 mmol) in batch. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was partitioned after 20 mL 2 M hydrochloric acid was dropwise added in an ice bath. The aqueous phase was extracted with 30 mL dichloromethane and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (12.7 g, yellow solid), yield: 72.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[C:10](O)(=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.[NH4+].[Cl-]>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[CH:3][CH:4]=1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: Nc1ccc(CO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(4-Aminophenyl)methanol (1 mmol) was taken up in 15 mL of CH2Cl2 along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (1 mmol) and HATU (1.1 mmol). The resulting reaction mixture was stirred at room temperature for 6 h and diluted with saturated aqueous NH4Cl. The two layers were separated and the organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded (4Z,7Z,10Z,13Z,16Z,19Z)—N-(4-(hydroxymethyl)phenyl)docosa-4,7,10,13,16,19-hexaenamide.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])=[CH:7][CH:6]=1)#[N:4]>C(O)C>[OH:2][NH:1][C:3](=[NH:4])[C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])=[CH:7][CH:6]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: NO
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=N)NO)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxylamine (50% w/w solution, 1 mL) was added to absolution of 3-(4-cyanophenoxy)-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (300 mg, 0.74 mmol) in ethanol (3 mL) and the reaction mixture allowed to stir at RT for 18 hours. The volatiles were removed in vacuo to give the desired compound as a colourless foam (325 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=O)[S:8][CH:9]=1)[CH3:2].Cl.[NH2:17]O.O>N1C=CC=CC=1.C(O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([C:10]#[N:17])[S:8][CH:9]=1)[CH3:2]
Reactant: NO
Reactant: CCCCC(CC)Cc1csc(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(CC)Cc1csc(C#N)c1
Temperature: 85 °C
Yield: 91.4 %

Procedure:
A mixture of 4-(2-ethylhexyl)-2-thiophenecarboxaldehyde (17.3 g, 77.1 mmol) and hydroxylamine hydrochloride salt (8.04 g, 116 mmol) in pyridine/ethanol (40 mL, 1/1, v/v) was refluxed at 85° C. for overnight. After cooling down to room temperature, the solution was rotary evaporated to remove most of the solvent. In a separatory funnel, the residue was taken up with chloroform (100 mL) and washed with distilled water (2×75 mL). After drying over anhydrous magnesium sulfate, the solvent was removed by rotary evaporation to give a yellowish liquid, which was dissolved in acetic anhydride (60 mL). To the resulting solution was added potassium acetate (0.4 g). The solution was then heated up to 140° C. and refluxed for 4 h. After cooling, the yellow solution was dropped into 100 mL of cold water and was extracted with hexane (2×100 mL). The combined organic layers were washed with distilled water twice and then dried over magnesium sulfate. The solvent was removed by rotary evaporation and the residue was subject to a silica-gel column chromatography (EtOAc/Hex=1/10, v/v, Rf=0.5) to yield a colorless liquid product (15.6 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.40 (d, 1H, J=1.2 Hz), 7.15 (d, 1H, J=1.2 Hz), 2.54 (d, 2H, J=6.8 Hz), 1.52 (m, 1H), 1.20-1.29 (m, 8H), 0.86 (m, 6H). (3-substitution isomer can be removed in chromatography.)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([N:19]=[N+]=[N-])[C:16](=[O:22])[C@H:15]2[C@@:6]1([CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:23])[CH2:13][C@@H:12]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[O:11][C:10]1=[O:29])=[O:4].[NH4+].[Cl-]>C(Cl)Cl.CO.[Zn]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:22])[C@H:15]2[C@@:6]1([CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:23])[CH2:13][C@@H:12]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[O:11][C:10]1=[O:29])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A mixture of 38 (0.08 g, 0.19 mmol), Zn dust (0.16 g, 2.45 mmol) and NH4Cl (g, mmol) in a mixture of CH2Cl2/MeOH (1:4, 20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. 2N NaOH (30 mL) was added to the residue and the mixture was extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 portion was washed with H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 0.06 g (84%) of 39 as a white solid, mp 237-240° C. (EtOAc/n-hexanes.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][CH:15]2[OH:20])C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][CH:15]2[OH:20]
Reactant: O=C(NC1CCC2CC1CCC2O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1CCC2CC1CCC2O
Yield: 105.4 %

Procedure:
0.72 g of (6-Hydroxy-bicyclo[3.3.1]non-2-yl)-carbamic acid benzyl ester (101) were dissolved in 50 mL of methanol and 97 mg of palladium on charcoal (10%) were added. The mixture was stirred under a hydrogen atmosphere until conversion was complete. The catalyst was filtered off and the organic layer was evaporated to dryness to give 407 mg of the desired product. Rt=0.17 min (Method C). Detected mass: 156.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:27][C:23]3[CH:22]=[C:21]([CH3:20])[N:26]=[CH:25][N:24]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]=2[N:10]=1
Reactant: Cc1cc(N)ncn1
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Temperature: 70 °C
Yield: 42.1 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.09 g, 0.25 mmol), 6-methylpyrimidin-4-ylamine (0.027 g, 0.25 mmol), XantPhos (0.015 g, 0.025 mmol) and Cs2CO3 (0.206 g, 0.625 mmol) in dioxane (2 mL) was degassed with a stream of argon. Pd2(dba)3 (0.012 g, 0.0125 mmol) was added and the reaction mixture was heated in a sealed vial at 70° C. for 5 hours. After allowing to cool to room temperature, a stream of argon was bubbled through the suspension and additional amounts of Pd2(dba)3 (0.010 g) and XantPhos (0.010 g) were added. The reaction mixture was heated at 80° C. for 18 hours. After cooling to room temperature, the crude mixture was filtered through Celite® washing with EtOAc and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in pentane and then triturated with diethyl ether to afford the title compound as an off-white solid (41 mg, 42% yield). 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.57-7.45 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.21 (t, J=8.7 Hz, 1H), 2.55 (s, 3H). LCMS (Method C): RT=3.54 min, m/z: 390 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (0.9 g) was obtained, melting point: 276° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)Cc1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of diisopropylamine (1.1 mL, 7.7 mmol) and tetrahydrofuran (20 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 4.5 mL, 7.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Tributyltin hydride (1.7 mL, 6.5 mmol) was added dropwise to the reaction mixture at the same temperature and then stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of 4-benzyloxybenzyl chloride (1.5 g, 6.5 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was gradually warmed to room temperature. The reaction mixture was partitioned into water and n-heptane. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:30) to obtain the title compound (2.6 g, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)Cc1cccc(F)c1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2cccc(F)c2)c(C)[nH]1
Yield: 78 %

Procedure:
4-[2-(3-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 78%. 1H (CDCl3, 400 MHz): δ 10.6 (NH, broad s), 7.30 (1H, s), 7.26 (1H, dd), 7.04 (1H, d), 6.99 (1H, d), 6.92 (1H, dd), 4.37 (2H, q), 4.07 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.5, 164.0, 161.6, 141.0, 137.4, 130.0, 125.3, 121.5, 120.5, 116.9, 116.4, 113.7, 61.0, 46.4, 14.4, 14.0 ppm. LC/MS: 98%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH2:8][CH2:9][C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=4)=[CH:23][C:6]2=3)=[CH:17][CH:18]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(Cl)cc1)CC2
Yield: 28.9 %

Procedure:
A solution of 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (35 mg, 0.16 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (60 mg, 0.16 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=12:1) to afford 5-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (9.3 mg, yield 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:19])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc([N+](=O)[O-])cc1
Yield: 84 %

Procedure:
3-(4-nitrophenyl)propanoic acid (500 mg, 2.56 mmol) was dissolved in MeOH (10 ml). SOCl2 (0.374 ml, 5.12 mmol) was added at 0° C., and the reaction was refluxed for 2 hours. The solvent was evaporated under vacuum, and the crude product was triturated in petroleum ether to give methyl 3-(4-nitrophenyl)propanoate (450 mg, 2.151 mmol, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.CCN(CC)CC>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=4)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(c5ccc(C#N)cn5)CC4C3)n2)cn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (377.4 mg, 1.13 mmol) and 6-chloronicotinonitrile (318.8 mg, 2.31 mmol) in a mixture of DCM and MeOH (10 mL/10 mL) was added Et3N (235.0 mg, 2.32 mmol). The reaction mixture was stirred at 45° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/80) to give the title compound as a beige solid (304.4 mg, 61.8%).
Reaction SMILES: [CH:1]1([N:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[N:10]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:15][C:13]1[CH:14]=[C:9]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][OH:8])[NH:10][C:11](=[O:17])[N:12]=1
Reactant: [OH-]
Reactant: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc(N(CCCO)C2CC2)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of 3-(cyclopropyl(2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (5.0 g, 19.07 mmol) in 1,4-dioxane (50 mL) was added a solution of NaOH (7.63 g, 191 mmol) in water (50 mL) at r.t, stirred for 4 h at 100° C. The organic solvent was removed under reduce vacuum and the PH was adjusted to 8 with aq. HCl (12 N). Purification via reverse C-18 column afforded the title compound (2.1 g) as a white solid.