Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:10]1[C:11]([I:13])=[CH:12][C:8]([NH2:3])=[N:9]1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2F)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cc(I)n(-c2ccccc2F)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole (1.23 g) in ethanol/water (2/1, 18 ml) were sequentially added hydroxylammonium chloride (4.47 g) and triethylamine (0.9 ml) at room temperature, and the mixture was stirred at 90° C. for 24 hours. This reaction mixture was cooled to room temperature, concentrated under reduced pressure. To the resulting residue was added a 8M aqueous solution of sodium hydroxide, and then the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/1) to give the titled compound (0.61 g).
Reaction SMILES: CO[C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C[CH:27]1[CH2:32][CH2:31][CH2:30]CC1(C)C.CC1(CC)CCCCC1.C(C1(CC)CCCCC1)C.N#N.[CH2:56]([NH2:60])[CH2:57][CH2:58][CH3:59]>CO.C1CCCCC1>[CH2:56]([N:60]([CH2:30][CH2:31][CH2:32][CH3:27])[C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[NH:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:57][CH2:58][CH3:59].[CH2:4]([NH2:5])[CH2:19][CH2:20][CH3:21]
Reactant: CC1CCCCC1(C)C
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)OC)C(=O)OC
Agent: CCC1(C)CCCCC1
Agent: CCC1(CC)CCCCC1
Agent: N#N
Solvent: CO
Solvent: C1CCCCC1
Solvent: CCCCN
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N(CCCC)CCCC

Procedure:
In a 1 I Quickfit flask with a glass-jacketed thermosensor, gas inlet, stainless steel anchor stirrer and heatable (67°-70° C.) pre-column with an attached Claisen bridge and subsequent cold trap, 110 g of N-lauroyl-L-glutamic acid dimethyl ester (LGA-DME) and 100 g of a mixture of cyclohexane derivatives (trimethylcyclohexane, methylethylcyclohexane and diethylcyclohexane in an approximate ratio of 45:25:10) are initially introduced under a gentle stream of N2. 110 g of n-butylamine are metered in over a period of 30 minutes and the mixture is heated under reflux. During the reaction, portions of the methanol liberated during the amidation are separated off, with a little n-butylamine, via the temperature-controlled pre-column. After refluxing for about 8 hours, monitoring by TLC indicates quantitative conversion. The excess n-butylamine is distilled off, first under normal pressure and then in vacuo, and the product is precipitated by addition of acetone. The precipitate formed is filtered off with suction, washed with acetone, dried and comminuted. The target product N-lauroyl-L-glutamic acid di-n-butylamide is obtained in a good yield of about 80% and in excellent purity (LGB 99% (HPLC), nBuNH2 50 ppm (GC), other impurities<1%) in the form of a colorless powder of melting point 150°-152° C.
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([CH3:34])[CH2:31][C@H:30]1[C:35]([OH:37])=[O:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:34][C@@H:32]1[CH2:33][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:35]([O:37][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:36])[CH2:31]1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a solution of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.32 g, 3.63 mmol) in MeCN (40 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.36 mmol) and DIPEA (0.7 mL, 3.99 mmol). After stirring for 18 h, the solution was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 40% EtOAc/hexanes) to afford (2S,4S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 4-methylpyrrolidine-1,2-dicarboxylate (1.31 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[S:17]([NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1)(=[O:19])=[O:18].Br[C:29]1[C:30]([CH3:36])=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:35][C:32]1[N:31]=[C:30]([CH3:36])[C:29]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:17]([NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([OH:27])[CH2:25][CH2:26]3)(=[O:18])=[O:19])[CH:4]=2)=[CH:34][N:33]=1
Reactant: CC1(C)OB(c2ccc(Cl)c(S(=O)(=O)NC3CCC(O)CC3)c2)OC1(C)C
Reactant: Cc1nc(N)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)NC2CCC(O)CC2)c1

Procedure:
The crude 2-chloro-N-(4-hydroxy-cyclohexyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide from step 2 (1.48 g), 5-Bromo-4 methyl-pyrimidin-2-ylamine (intermediate C) (0.669 g, 3.36 mmol) and PdCl2(dppf).DCM (0.436 g, 0.53 mmol) are placed in a microwave vial containing degassed DME (10 ml) and 2M Na2CO3 (2 ml). The resulting mixture is heated using microwave radiation at 100° C. for 15 minutes. After evaporation of the solvent, the reaction mixture is purified by flash chromatography on silica eluting with ethanol to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C@H:40]2[CH2:45][CH2:44][C@H:43]([O:46][CH2:47][CH3:48])[CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:47]([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:37]3[C:33]=2[CH2:34][N:35]([CH3:39])[C:36]3=[O:38])[CH2:45][CH2:44]1)[CH3:48]
Reactant: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(trans-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166B). 1H NMR (DMSO-d6, 400 MHz): δ=1.11 (t, J=6.95 Hz, 3 H), 1.18 (t, J=6.95 Hz, 6 H), 1.21-1.33 (m, 2 H), 1.54-1.68 (m, 2 H), 1.80 (d, J=12.63 Hz, 2 H), 2.09 (dd, J=12.63, 3.28 Hz, 2 H), 3.08 (s, 3 H), 3.18-3.27 (m, 2 H), 3.49 (q, J=6.99 Hz, 2 H), 3.91-4.01 (m, 4 H), 4.52 (s, 2 H), 7.26 (dd, J=8.72, 1.89 Hz, 2 H), 7.40 (d, J=8.59 Hz, 1 H), 7.56 (br. s., 2H), 8.45 (s, 1 H), 8.67 (s, 1 H), 9.89 (s, 1 H), 10.58 (br. s., 1 H). MS (ES+): m/z 676.25 [MH+] (TOF, polar).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH2:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:38]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)[CH3:39]
Reactant: CCN
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), ethanamine-HCl (5.36 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.4) to provide (R/S)-N-ethyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (8 mg, 0.015 mmol, 33.5% yield): LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.23 (2 H, m), 7.52-7.74 (7 H, m), 5.11 (1 H, s), 3.43-3.57 (2 H, m), 3.17 (2 H, q, J=7.41 Hz), 2.40 (2 H, t, J=6.71 Hz), 1.09 (3 H, t, J=7.26 Hz); HPLC peak RT=8.6 min (Method A).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])[CH:5]=[CH:4]1.[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([C:40]4[NH:44][N:43]=[N:42][N:41]=4)[CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:25]1([N:28]2[C:36]3[C:31](=[C:32]([C:40]4[NH:44][N:43]=[N:42][N:41]=4)[CH:33]=[C:34]([C:37]([N:17]4[CH2:18][CH2:19][C:14]5([CH2:13][C:12](=[O:24])[C:11]6[C:21](=[CH:22][CH:23]=[C:9]([C:6]7[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=7)[CH:10]=6)[O:20]5)[CH2:15][CH2:16]4)=[O:38])[CH:35]=3)[CH:30]=[CH:29]2)[CH2:26][CH2:27]1
Reactant: O=C(O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3ccc(=O)[nH]c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(C(=O)c3cc(-c4nnn[nH]4)c4ccn(C5CC5)c4c3)CC2)Oc2ccc(-c3ccc(=O)[nH]c3)cc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-(6-Oxo-1,6-dihydropyridin-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (208 mg), 1-cyclopropyl-4-(tetrazol-5-yl)-1H-indole-6-carboxylic acid (135 mg), EDCI (115 mg), HOBT (91.2 mg) and triethylamine (0.209 ml) were suspended in DMF (3 ml), and stirred at 50° C. for 16 hours. 1N hydrochloric acid and water were added to the reaction liquid, the formed solid was taken out through filtration, and the resulting solid was recrystallized from methanol to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 11.78 (1.0H, s), 7.85-7.82 (2.0H, m), 7.81-7.75 (3.0H, m), 7.67 (1.0H, d, J=2.4 Hz), 7.64 (1.0H, d, J=3.2 Hz), 7.17-7.11 (2.0H, m), 6.40 (1.0H, d, J=9.5 Hz), 4.46-4.12 (1.0H, m), 3.93-3.13 (4.0H, m), 2.92 (2.0H, s), 2.15-1.90 (2.0H, m), 1.88-1.75 (2.0H, m), 1.16-1.08 (2.0H, m), 1.04-0.98 (2.0H, m). MS [M+H]+=562.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])[N:3]=1.[Br:22]Br>CO>[NH2:1][C:2]1[C:7]([Br:22])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:11])[N:3]=1
Reactant: CC(Sc1nc(N)cc(Cl)n1)c1cc2ccccc2cn1
Reactant: BrBr
Solvent: CO
Product: CC(Sc1nc(N)c(Br)c(Cl)n1)c1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
4-Amino-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine (475 mg, 1.5 mmole) is suspended in 15 ml methanol in a 50 ml one neck round bottom flask under nitrogen at 0° C. The suspension is treated slowly dropwise with bromine (85 μl, 1.65 mmole) and the reaction mixture is stirred 20 min at 0° C. The volatiles are removed in vacuo and the residue is partitioned between 1×50 ml dichloromethane and 1×50 ml saturated sodium carbonate followed by 1×50 ml saturated sodium thiosulfate. The organic layer is dried over potassium carbonate and is concentrated in vacuo to a white foam. Crystallization from 1:9 diethyl ether/hexane afforded 513 mg (86%) of 4-Amino-5-bromo-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8](SC)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1.O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(c1)Nc1cscc1C(SC)=N2
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)Nc1cscc1C(N1CCN(C)CC1)=N2

Procedure:
A solution of 6-methoxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-methylpiperazine and glacial acetic acid is heated at reflux for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [I-].[Li+].[CH3:3][C:4]1([CH3:33])[S:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:5]1[C:29]([O:31]C)=[O:30]>>[CH3:3][C:4]1([CH3:33])[S:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)(=[O:11])=[O:12])[C@H:5]1[C:29]([OH:31])=[O:30]
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)[C@H]1C(=O)O
Yield: 79.1 %

Procedure:
According to the procedure of Example 250, lithium iodide mediated ester cleavage of 0.282 g (0.61 mmol) of methyl(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholinecarboxylate provided 0.215 g (79%) of (3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 446.0 (N+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20].[NH2:30]/[C:31](/[CH3:40])=[CH:32]\[C:33]([O:35]CCC#N)=[O:34]>C(O)(C)C.C([O-])(=O)C.[NH2+]1CCCCC1>[C:11]([NH:10][CH2:9][CH2:8][O:7][C:1]([C:2]1[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:32]([C:33]([OH:35])=[O:34])=[C:31]([CH3:40])[NH:30][C:3]=1[CH3:5])=[O:6])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCNC(=O)c1cccnc1
Reactant: C/C(N)=C/C(=O)OCCC#N
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2cccnc2)=C(C)N1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 25.03 g (100 mole) of 2-nicotinoylaminoethyl acetoacetate, 15.11 g (100 mmole) of m-nitrobenzaldehyde and 15.42 g (100 mmole) of 2-cyanoethyl 3-aminocrotonate in 150 ml of isopropyl alcohol was added 0.73 g (5 mmole) of piperidinium acetate, and the mixture was refluxed for 5 hours. After evaporation of the solvent, the residue was dissolved in 200 ml of acetone. To the solution was added 200 ml of 0.75 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for an hour. 1N hydrochloric acid was added, and the solution was concentrated and extracted with chloroform Evaporation of the solvent gave 45.27 g of 2,6-dimethyl4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-nicotinoylaminoethyl) ester.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+]>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:16][C:17]([OH:19])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a stirred, 0° C. solution of (S)-4-phenyloxazoldin-2-one (1.07 g, 6.54 mmol) in 15 mL of THF was added sodium hydride (0.32 g of a 60% oil dispersoin, 8.0 mmol). When gas evolution had ceased (ca. 10 minutes), ethyl bromoacetate (0.87 mL, 7.8 mmol) was added. After 2 hours at 0° C., the mixture was treated with 50 mL of 2N aqueous NaOH, stirred rapidly for 1 hour at room temperature, and then partitioned between hexane (50 mL) and water (50 mL). The aqueous layer was separated, acidified with 6M aqueous H2SO4, and extracted with dichloromethane (2×200 mL). The combined organic phases were dried (Na2SO4) and concentrated to a thick oil, which was dissolved in 4 mL of warm toluene, seeded, and allowed to crystallize overnight; filtration gave 1.33 g (92%) of (S)-4-phenyloxazolidin-2-one-3-ylacetic acid: mp 106°-108° C.;
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C(O)=O.C(=O)([O-])[O-].[Li+].[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 95.5 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (30 g, 0.11 mols), formic acid (9.7 g, 0.21 mols), lithium carbonate (7.8 g, 0.11 mols) and methanol (180 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (6 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 4 hours. Water (10 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (30 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (20 g, yield 100% by mass). The result is shown in Table II-2.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:30]3[C:22]([CH3:21])=[CH:23][NH:24][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: Cc1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.7 mmol) in toluene (21 mL) and EtOH (7 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine 21 (0.7 g, 2.37 mmol in theory) and 2 N aq. Na2CO3 (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.19 g, 0.17 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-5) (0.150 mg, 16.2%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[CH:7]=2)=[O:31])=[N:28][CH:29]=1)#[N:23]
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1(F)F

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17B) (150 mg, 0.47 mmol) and commercially available 5-cyano-pyridine-2-carboxylic acid [CAS No. 53234-55-2] (105 mg, 0.71 mmol). The compound was obtained as a light brown oil (280 mg, 99%, 75% purity). MS (ISP): m/z=449.2 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=[O:27])[C:5]1[CH:6]=[C:7]3[C:25](=[O:26])[O:24][C:22](=[O:23])[C:8]3=[CH:9][C:10]=1[C:11]2=[O:21].[CH2:28]([OH:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].S(=O)(=O)(O)O.O>CO>[CH2:28]([O:36][C:22]([C:8]1[C:7]([C:25]([O:24][CH2:18][CH2:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:10][CH3:9])=[O:26])=[CH:6][C:5]2[C:4](=[O:27])[C:3]3[C:12](=[C:13]([OH:20])[C:14]4[C:19]([C:2]=3[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=[O:21])[C:10]=2[CH:9]=1)=[O:23])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCO
Reactant: O=c1oc(=O)c2cc3c(=O)c4c(O)c5ccccc5c(O)c4c(=O)c3cc12
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCCCCCOC(=O)c1cc2c(cc1C(=O)OCCCCCCCC)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Reaction time: 18 h
Yield: 164.6 %

Procedure:
1.89 g (5.2 mmoles) of 6,11-dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid anhydride (product of example 9), 6.77 g (52 mmoles) of 1-octanol, and 0.2 g (2.08 mmoles) of 96% sulfuric acid are refluxed for 3 h with azeotropic removal of the reaction water. The mixture is kept at 25° for 18 h, then stirred with methanol and filtered. The precipitate is washed with water and dried in vacuo to give 2.58 g (81%) of red crystals, m.p. 95-96°.