Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](O)=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([Cl:21])=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Product: O=c1c([N+](=O)[O-])c(Cl)ccn1Cc1ccccc1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A suspension of 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 13.4 mmol) in POCl3 (30.8 g, 201 mmol) was heated at for 1 h. After cooling to room temperature, the solvent was evaporated under reduced pressure, and water was carefully added to the chilled residue. The mixture was neutralized with 2 N NaOH, extracted with CHCl3, washed with brine, dried with MgSO4, and concentrated under reduced pressure. The resulting solid was rinsed with Et2O to give 1-benzyl-4-chloro-3-nitro-1H-pyridin-2-one (1.31 g, 37% yield). 1H-NMR (CDCl3): δ 7.36 (m, 6H), 6.29 (d, 1H, J=7.6 Hz), 5.16 (s, 2H). MS: calculated for C12H9ClN2O3+H 265.0; found: 265.1.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Solvent: CC(=O)O
Product: CCC(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)c3ccccc3n4CC)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 440.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc2[nH]ncc2cn1
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Yield: 89.5 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.3 g, 2 mmol) (Frontier Cat. No. Z13659) and N-iodosuccinimide (0.53 g, 2.3 mmol) in N,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 h. After cooling it was concentrated and the residue was treated with methanol. The white solid was collected by filtration to afford the desired product (0.5 g). LCMS (M+H)+=279.9.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[C:6]1([NH2:24])[N:7]=[C:8]([NH2:23])[N:9]=[C:10]2[C:22]=1[C:21]1[C:20]3C[CH2:18][CH2:17][CH2:16][C:15]=3NC=1[CH:12]=[CH:11]2.[H-].[Na+].CI>C(O)(=O)C>[CH3:1][N:2]1[C:5]2[CH:12]=[CH:11][C:10]3=[N:9][C:8]([NH2:23])=[N:7][C:6]([NH2:24])=[C:22]3[C:21]=2[C:20]2[CH2:15][CH2:16][CH2:17][CH2:18][C:3]1=2
Reactant: CN(C)C=O
Reactant: Nc1nc(N)c2c(ccc3[nH]c4c(c32)CCCC4)n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: Cn1c2c(c3c4c(N)nc(N)nc4ccc31)CCCC2
Reaction time: 2 h

Procedure:
Dry dimethylformamide (150 ml.), 4.62 g. 8,9,10,11-tetrahydro-7H-pyrimido[4,5-c]carbazole-1,3-diamine and 0.96 g. ca. 50% sodium hydride-mineral oil dispersion are stirred, under nitrogen, for 1 hour. A solution of 2.84 g. methyl iodide in 10 ml. dry dimethylformamide is added during 10 minutes and stirring is continued for ca. 2 hours. Glacial acetic acid (20 ml.) is added and the solvent is removed. The residue is stirred with 12 g. sodium methoxide-150 ml. methanol for 2 hours and the mixture is diluted with 750 ml. water. The solids are collected, washed with water, dried, twice recrystallized from methanol and thoroughly dried to yield 1.96 g. title compound, m.p. 288°-292° (softens 285°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(3-fluorophenoxy)benzoate (0.202 g; 0.880 mmol) was added to a mixture of NaOH in water (2 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated under reduced pressure and dissolved in water. The aqueous layer was acidified with a solution of hydrogen chloride 6M and the precipitated product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a grey solid which was used without further purification.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.C1COCC1.CO.[OH-].[Na+]>C(OCC)(=O)C>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH2:8][OH:7])([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate from above reaction was added THF:MeOH (1:1, 2 mL) and 2M NaOH (0.5 mL) were added and reaction mixture was heated at 55° C. for 3 h. Reaction mixture was cooled to rt, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (EtOAC/Hex) to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethanol (15 mg). LCMS-ESI+: calc'd for C33H32ClN4O2S: 583.2 (M+H+); found: 583.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[OH-:25].[Na+]>O1CCCC1>[Cl:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:25])[CH:7]=1
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of 5,7-dichloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (1.30 g, 3.47 mmol) in tetrahydrofuran (25 ml) was added sodium hydroxide solution (3 mL, 17.37 mmol). The reaction mixture was stirred at 50° C. for 3 hours. Solvent was removed. The residue was dissolved with ethyl acetate (50 mL) and 5% HCl solution (20 mL). Organic layer was separated and dried. The crude material was purified on silica gel column (methanol/DCM, 0-10% gradient solvent system) to give the product. It was used for next step. (0.88 g, 68%); LC/MS: MS (ES+) m/e 356 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]3)[N:10]=2)[CH:7]=1.[N:18]1(C2N=C3C=CC(N)=CN3N=2)CCOCC1>>[CH3:17][O:16][CH:13]1[CH2:14][CH2:15][N:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH2:18])=[CH:7][N:6]3[N:8]=2)[CH2:12]1
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: COC1CCN(c2nc3ccc(Br)cn3n2)C1
Product: COC1CCN(c2nc3ccc(N)cn3n2)C1

Procedure:
Using 6-Bromo-2-(3-methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine, this compound was prepared following the same method as for the synthesis of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine. Brown solid (1.4 g, 71%). MS: m/z=234 (M+H+).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[CH2:53]2)=[CH:48][CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:55]=[C:54]3[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:58])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (DMSO as solvent; purification via HPLC) from 3.00 g (14.8 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 4.54 g (14.8 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([OH:23])=O)[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:24])/[C:21]([NH:32][O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)=[O:23])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1
Reactant: O=C(O)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
A mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (658 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (229 mg), HOBt (264 mg) and EDCI (303 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4 The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg).
Reaction SMILES: C([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:54]=[CH:53][C:10]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([O:35]CC4C=CC=CC=4)[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>CO.ClCCl.[Pd]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([OH:35])[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2[CH:53]=[CH:54][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 224.5 %

Procedure:
Sodium formate (1.2 g) was added to a mixture of compound 24 (1.02 g, 0.52 mmol) and Pd/C (10%, 0.5 g) in methanol (20 mL). The mixture was refluxed for 20 min, cooled to room temperature and diluted with dichloromethane (20 mL). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a white solid material, which was crystallised from 50% ethanol/water to yield 680 mg (77%) of compound 25.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.O>CN(C=O)C>[CH:15]1([NH:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccncc1
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1cc(NC2CC2)ccn1

Procedure:
To a magnetically stirred, 25° C. solution of 2.3 g (0.006 mol) of product of Step A and 0.71 g (0.007 mol) of triethylamine in 40 ml of DMF was added dropwise 0.38 g (0.007 mol) of cyclopropylamine. After 18 hours the reaction mixture was poured into H2O and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 1.95 g of a brown solid. The crude was recrystallized from hexane/EtOAc affording 1.2 g (50%) of product as a beige solid; mp 111°-112° C.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1>C1(C)C=CC=CC=1>[CH:1]1([C:6]2[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCC3)cs2)c1
Yield: 86.8 %

Procedure:
A solution of 2.7 g of (E)-3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 40 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 3.75 g of (E)-2-[2-[3-[2-[4-(cyclopentyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 209°-210° C. from tetrahydrofuran.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13].[C:28](=[O:31])([O-])[O-].[Cs+].[Cs+].[C:34]1(C)[CH:39]=CC=C[CH:35]=1.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.C(O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:12]([N:15]([C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13])=[C:2]([CH:35]=[CH:34][CH2:39][O:31][CH3:28])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: COCC=Cc1cc(C(C)(C)C)ccc1S(=O)(=O)N(COC)c1ccsc1C(=O)OC

Procedure:
Synthesized as described for 7 using 6 (300.0 mg, 0.65 mmol), cesium carbonate (634.0 mg; 1.95 mmol), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (193.0 mg; 0.97 mmol), tetrakis(triphenylphosphine)palladium(0) (37.0 mg; 0.032 mmol), toluene (1.5 mL), water (1.5 mL) and ethanol (1.5 mL). The crude dark oil was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 20% v/v gradient elution over 500 mL) to give the title compound as a yellow oil (189 mg).
Reaction SMILES: C([O:5][C:6](=[O:46])[C@H:7]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:8][CH2:9][CH:10]1[C:22]2[C:17](=[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]3=[C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]3=2)[C:16]2[C:11]1=[C:12]1[CH:38]=[CH:37][CH:36]=[CH:35][C:13]1=[C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]1=2)(C)(C)C>FC(F)(F)C(O)=O.O.C(OCC)C>[CH:23]1[C:21]2[C:20](=[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]3=[C:17]3[C:22]=2[CH:10]([CH2:9][NH:8][C@H:7]([C:6]([OH:46])=[O:5])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:11]2[C:16]3=[C:15]3[CH:31]=[CH:32][CH:33]=[CH:34][C:14]3=[C:13]3[CH:35]=[CH:36][CH:37]=[CH:38][C:12]3=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)[C@H](Cc1ccccc1)NCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21

Procedure:
A solution of Nα-17-tetrabenzo(a,c,g,i)fluorenylmethyl-L-phenylalanine tert-butyl ester (421.1 mg, 0.702 mmol) in trifluoroacetic acid (3.6 ml) and water (0.2 ml) was sonicated for 3.5 h at room temperature. The solvent was removed in vacuo to give a brown residue. Trituration in diethylether gave the compound (53) as a yellow solid which was chilled overnight, filtered, washed with ether, and finally dried (352.7 mg, 92%);
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A mixture of 3.2 g (12 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid, 1.4 ml (10 mmol) of triethylamine, 1.5 g (10 mmol) of 5-amino-1,3-dihydro-indol-2-one [Tetrahedron, 24, 1376. (1957)] 3.8 g (10 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] and 100 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 150 ml of 8% sodium hydrogencarbonate solution and 150 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 25 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and chloroform:methanol=19:1 as eluent to yield 2.67 g (68%) of the title compound. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CO.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:35]4[CH2:36][CH2:37][O:32][CH2:33][CH2:34]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C

Procedure:
To a suspension of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (2.50 g, 6.0 mmol) in a mixed solvent of MeOH (42 mL) and DCM (10 mL) was added dihydro-2H-pyran-4(3H)-one (3.33 mL, 36.0 mmol) and TEA (8.36 mL, 60.0 mmol). The reaction mixture was heated at 60° C. for 1 h before NaCNBH3 (1.66 g, 26.4 mmol) was added. The mixture was heated at 60° C. for another 2 h, cooled down to room temperature, diluted with DCM (60 mL), dry loaded onto silica gel (12.5 g), and purified by silica gel chromatography (DCM with 1% NH3 to 10% MeOH in DCM with 1% NH3 gradient) to provide 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; 1H NMR (DMSO-d6, 400 MHz) δ 12.08 (br, 1H), 9.58 (br, 1H), 8.65 (d, J=28.4 Hz, 1H), 8.02 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.03 (d, J=12.4 Hz, 1H), 6.08 (br, 1H), 3.89 (dd, J=10.8, 3.6 Hz, 2H), 3.28 (t, J=10.4 Hz, 2H), 2.99 (d, J=10.8 Hz, 2H), 2.64-2.43 (m, 2H), 2.24-2.15 (m, 8H), 1.71-1.40 (m, 8H); ESMS m/z 500.2 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:6]([CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[N:11]=1)[CH2:7]O)[CH:2]=[CH2:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C@H:5]1[CH2:24][N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:7][C@H:6]1[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H](CNCc1ccccc1)[C@@H](CO)Cc1cc(C)cc(-n2c(C)ccc2C)n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCO[C@H]1CN(Cc2ccccc2)C[C@H]1Cc1cc(C)cc(-n2c(C)ccc2C)n1
Reaction time: 0.03 h
Yield: 100 %

Procedure:
To a solution of 20 (70 mg, 0.16 mmol) in CH2Cl2 (2.0 mL) at room temperature was added MsCl (15 μL, 0.19 mmol). After 2 min, triethylamine (34 μL, 0.24 mmol) was added dropwise as a solution in CH2Cl2 (340 μL). The reaction was allowed to stir for another 2 min and concentrated by rotary evaporation. The crude material was purified by flash column chromatography (EtOAc:hexanes, 2:1-4:1) to give 2 (66 mg, 0.16 mmol, 100%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.12 (s, 6H), 2.38 (s, 3H), 2.38-2.43 (m, 1H), 2.53-2.56 (dd, J=3.0, 10.0 Hz, 1H), 2.77-2.80 (dd, J=7.5, 8.0 Hz, 1H), 2.80-2.91 (m, 2H), 3.08-3.13 (m, 2H), 3.79-3.83 (dd, J=5.5, 13.0 Hz, 1H), 3.97-3.99 (br s, 2H), 5.14-5.16 (dd, J=1.0, 10.0 Hz, 1H), 5.23-5.26 (dd, J=1.0, 17.0 Hz, 1H), 5.80-5.89 (m, 1H), 5.89 (s, 2H), 6.84 (s, 1H), 7.00 (s, 1H), 7.20-7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 36.2, 42.5, 58.4, 60.2, 61.0, 70.9, 79.1, 98.9, 106.8, 116.7, 120.1, 123.4, 127.1, 128.5, 128.7, 128.9, 135.2, 149.4, 151.8, 161.3; LCQ-MS (M+H+) calcd for C27H34N3O 416. found 416; LC-TOF-MS (M+H+) calcd for C27H34N3O 416.27019. found 416.26956.