Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH3:45][O:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:49]2[CH2:50][CH2:51][CH2:52][C@@H:47]([O:46][CH3:45])[CH2:48]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CO[C@@H]1CCCNC1
Solvent: CC#N
Product: CO[C@@H]1CCCN(C(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C#N)[C@H]2c2ccc(C#N)cc2S(C)(=O)=O)C1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with (3R)-3-methoxypiperidine (44.2 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (45 mg, 57% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(OO)=[O:14].CC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: [O-][n+]1cc(Br)cc2ccccc21
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 3-Bromoquinoline 5 (2.08 g, 10 mmol) in CHCl3 (5 ml) was added CH3CO2OH (5 ml, 32% solution in dilute HOAc, 20 mmol) and the mixture was stirred overnight. Acetone (3 ml) was added and the mixture was stirred an additional 15 min then poured into saturated NaHCO3 (aq) and extracted with CH2Cl2. The combined extracts were dried (K2CO3) and concentrated to yield pure 6 (2.26 g, 100%) as a tan solid. 1H NMR d (d=delta) (ppm): 7.7 dd (CH atom), 7.8 m (2 CH atom), 7.9 s (CH atom), 8.6 s (CH atom), 8.7 d (CH atom).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]([CH3:16])=[N:9][CH:8]=1)=O.Cl.[NH2:19][C:20]([NH2:22])=[NH:21].C[O-].[Na+]>C(O)CCC>[NH2:21][C:20]1[N:22]=[C:5]([C:7]2[N:11]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[C:10]([CH3:16])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:19]=1
Reactant: N=C(N)N
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(N)n2)n1C1CCC1
Temperature: 25 °C
Yield: 65640 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37; 466 mg, 2 mmol) and guanidine hydrochloride (476 mg, 5 mmol) were suspended in 1-butanol (10 ml). Sodium methoxide (432 g, 8 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 2 hours. The reaction mixture was allowed to cool to ambient temperature and was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to give the title compound (301 g, 66%). NMR: 1.73 (m, 2H), 2.45 (m, 7H), 5.36 (m, 1H), 6.58 (s, 2H), 6.72 (d, 1H), 7.24 (s, 1H), 8.16 (d, 1H); m/z 230
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:5]2.B([C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([OH:35])=[O:34])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1)(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[N:6]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:5]4)[CH:21]=2)=[CH:27][C:28]=1[C:33]([OH:35])=[O:34]
Reactant: O=C1c2ccc(Br)cc2CN1C1CCCC1
Reactant: O=C(O)c1cc(-c2cccc(B(O)O)c2)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1cc(-c2cccc(-c3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl
Temperature: 75 °C
Yield: 12.3 %

Procedure:
5-Bromo-2-cyclopentylisoindolin-1-one (76 mg, 0.27 mmol), 3′-borono-4-chlorobiphenyl-3-carboxylic acid (90 mg, 0.33 mmol), Cs2CO3 (268 mg, 0.82 mmol) and PdCl2(PPh3)2 (22 mg, 0.03 mmol), were dissolved in a mixture of DME-H2O-EtOH (9.1 mL:3 mL:2.2 mL) and heated at 75° C. for 2 hours. The mixture was filtered through celite washed with water and filtrate was acidified with 2.5 M HCl to form the crude acid as a yellow solid. The crude residue was purified using automated prep-HPLC to yield the desired compound (14.3 mg, 12%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J=2.3 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.78-7.54 (m, 8H), 4.84-4.75 (m, 1H), 4.43 (s, 2H), 2.08-2.00 (m, 2H), 1.83-1.62 (m, 6H). LRMS calcd. for C26H22ClNO3 [M+H]+ 432 found: 432.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[Cl:25][C:26]1[C:27]([O:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:25][C:26]1[C:27]([O:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[N:28][C:29]([NH:32][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:30][CH:31]=1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: Nc1ncc(Cl)c(OC2CCOC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ncc(Cl)c(OC3CCOC3)n1)CCC2
Reaction time: 0.33 h

Procedure:
A solution of phenyl 7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 3, 11.4 mg, 0.035 mmol) and 5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 30, 7.5 mg, 0.035 mmol) in THF (1.5 ml) at room temperature under argon was treated drop wise with LHMDS (1 M in THF, 0.10 ml, 0.10 mmol). The reaction mixture was stirred for 20 min, quenched by addition of sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.10 min; ESI-MS 450.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:63])[CH2:40][C@H:41]([OH:62])[C@@H:42]([NH:50][C:51](=[O:61])[C@H:52]([CH:58]([CH3:60])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[CH3:59][CH:58]([C@H:52]([NH:53][C:54]([O:56][CH3:57])=[O:55])[C:51]([NH:50][C@H:42]([C@@H:41]([OH:62])[CH2:40][N:39]([NH:63][C:10]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:11])[CH2:38][C:35]1[CH:34]=[CH:33][C:32]([C:28]2[S:27][CH:31]=[CH:30][N:29]=2)=[CH:37][CH:36]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:61])[CH3:60]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7,140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2.2 ml of DMF and 418 μl (3.0 mmol) of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 4.5 ml of DMF to form the title compound: m.p: 207-210° C.; HPLC20-100 : tRet =13.8; FAB MS (M+H)+ =683.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:13]=2)[CH:9]=[N:8]1.Cl[CH2:48][C:49]([NH2:51])=[O:50].C(=O)(O)[O-].[Na+]>CC(C)=O.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=4)[CH2:27][CH:28]4[CH2:29][CH2:30][N:31]([CH2:48][C:49]([NH2:51])=[O:50])[CH2:32][CH2:33]4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCNCC5)c4)cnc32)cc1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(CC(N)=O)CC5)c4)cnc32)cc1
Yield: 38.9 %

Procedure:
Using the same reaction conditions as described in step-i of example-82A 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(piperidin-4-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (75 mg, 0.114 mmol) was alkylated using 2-chloroacetamide (16 mg, 0.171 mmol) and sodium bicarbonate (29 mg, 0.342 mmol) in acetone/ethanol (5/5 mL) to get 30 mg (38.96% yield) of the titled compound. MS: m/z=676.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=O)=[O:9])=[CH:4][CH:3]=1.O>CN1C(=O)CCC1>[CH:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])[CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(S(=O)c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
At room temperature, 10.85 g (20 mmol) of bis[4-(3,4-dicarboxyphenoxy)phenyl]sulfonic acid dianhydride (SOPOP) was added to a solution of 4.966 g (20 mmol) of bis(4-aminophenyl) sulfone (DDSO) in 68 ml of NMP. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was dropwise added to 1.5 liters of water to obtain a polyamic acid (SOPOP/DDSO) as a solid product in a yield of 14.2 g.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2ccccc2Cl)nn1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2Cl)nn1

Procedure:
A solution of 19.8 g. of 3-chloro-6-(o-chlorophenyl)-1,2,4-triazine in 120 ml. of pyridine is treated with 15 g. of hydrazine hydrate as described in Example 12, giving 6-(o-chlorophenyl)-3-hydrazino-1,2,4-triazine as yellow needles.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:6]=12.[C:22]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:11][C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:23]#[C:22][C:24]3[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)cnn12
Reactant: C#Cc1cnc(N)nc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3cnc(N)nc3)cnn12

Procedure:
The title compound was prepared from 3-iodo-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12 step 2) (202 g, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2, step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (90 mg, 46%). MS (ISP) 395.0 [(M+H)+]; mp 246-248° C.
Reaction SMILES: [CH2:1]([C:3]1([CH:14]2C(=O)OC(C)(C)[O:16][C:15]2=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].CN(C=O)C.O>CCOC(C)=O>[CH2:1]([C:3]1([CH2:14][C:15]([OH:23])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(C2C(=O)OC(C)(C)OC2=O)CCc2ccc(OC)cc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1(CC(=O)O)CCc2ccc(OC)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A 100 mL round bottom flask was charged with 42.1 (0.30 g, 0.94 mmol) and 10:1 DMF/water (5 mL). The solution was stirred overnight at 90° C., cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to afford 42.2 (0.204 g, 92% yield) as a yellow oil.
Reaction SMILES: COS([O-])(=O)=O.[CH3:7][N+:8]1[N:9]([CH3:25])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH+]1NC=CC=1.[Cl:32][C:33]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:34]=1[O:35][CH2:36][C:37]([OH:39])=[O:38]>O>[Cl:32][C:33]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:34]=1[O:35][CH2:36][C:37]([O-:39])=[O:38].[CH3:25][N+:9]1[N:8]([CH3:7])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: COS(=O)(=O)[O-]
Agent: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Agent: [OH-]
Solvent: O
Product: O=C([O-])COc1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
1,2-Dimethyl-3,5-diphenylpyrazolium methyl sulfate was converted by ion exchange chromatography to the pyrazolium hydroxide. This was then titrated (H2O solution) with 2,4-dichlorophenoxyacetic acid. Solid 2,4-D was added and went into solution after a very short time. The pH of the solution was monitored using a pH meter. Addition of the acid was stopped at pH 7 (initially pH was 12 to 13). This H2O solution was kept at room temperature for 48 hours. The pH was then approximately 8. An additional amount of acid was added until pH 7 was again obtained. After 24 hours, pH held at 7. ##STR6## The H2O solution was evaporated to a yellow oil and then azeotroped with toluene/acetone several times. Hexane was added with 5% to 10% dry acetone. The oil solidified to a white solid, was filtered, washed with hexane/acetone and dried. 7.0 Grams, melting point 152° C. to 154° C., of a lemon yellow solid was obtained.
Reaction SMILES: [NH:1]([C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)[NH2:2].[CH2:13]([O:15][C:16](=[O:25])[C:17](=O)[CH2:18][C:19](=O)[CH:20]([CH3:22])[CH3:21])[CH3:14]>C1(C)C=CC=CC=1>[CH3:10][O:9][C:6]1[N:5]=[C:4]([O:11][CH3:12])[C:3]([N:1]2[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:25])=[N:2]2)=[CH:8][N:7]=1
Reactant: COc1ncc(NN)c(OC)n1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(C)C)n(-c2cnc(OC)nc2OC)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
5-hydrazinyl-2,4-dimethoxypyrimidine (Step 46.8) (140 g, 823 mmol) was dissolved in toluene (3 L) under nitrogen atmosphere and ethyl-2,4-dioxo-5-methylhexanoate (230 g, 1234 mmol) was added dropwise over 15 min. The reaction mixture was heated up and stirred at 110° C. for 1 hr. The brown solution was quenched with saturated aq. NaHCO3 solution (2 L) and extracted with EtOAc (2×2 L). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was stirred in hexane (1 L) at RT and the resulting suspension was filtrated off and dried to afford the title product (193 g, 596 mmol, 72% yield) as white crystals. tR: 1.01 min (LC-MS 1); ESI-MS: 321 [M+H]+ (LC-MS 1).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16](CC3C=CC(OC)=CC=3OC)[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:33]#[N:34])=[C:4]([C:37]2[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=2)[CH:3]=1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.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:33]([C:8]1[CH:9]=[C:10]([S:13]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:15])=[O:14])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:35]=[CH:36][C:2]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[CH:3][C:4]=1[C:37]1[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=1)#[N:34]
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
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: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 4-[4-bromo-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-3-cyano-N-(2,4-dimethoxy-benzyl)-N-thiazol-2-yl-benzenesulfonamide (Preparation 88, 98.5 mg, 0.148 mmol), 2-methoxyphenylboronic acid (48 mg, 0.32 mmol), and potassium carbonate (62.5 mg, 0.452 mmol) in toluene (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (22.5 mg, 0.0195 mmol) and the mixture was sparged two times with argon. The reaction mixture was then heated at reflux for 4.5 hours and then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by automated flash column chromatography using a 0-100% EtOAc/hexanes gradient to give a clear oil. This oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (1 mL, 10 mmol). After stirring for 1 hour, the reaction mixture was concentrated in vacuo and purified by automated flash column chromatography (0%-5% methanol in dichloromethane gradient elution) to yield the title compound (50 mg, 61%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9](=[O:11])[CH3:10])=[CH:7][N:6]=[C:5]1[CH2:12][O:13][CH3:14])([CH3:3])[CH3:2]>CN(C=O)C>[CH3:1][N:4]([CH3:8])[CH:5]=[CH:10][C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH2:12][O:13][CH3:14])=[N:6][CH:7]=1)=[O:11]
Reactant: COCc1ncc(C(C)=O)n1C(C)C
Solvent: CN(C)C=O
Product: COCc1ncc(C(=O)C=CN(C)C)n1C(C)C
Yield: 105.3 %

Procedure:
1-Isopropyl-2-methoxymethyl-5-acetylimidazole (Method 12; 3.34 g, 17 mmol) was dissolved in a mixture of DMF (34 ml) and DMF.DEA (11.5 ml, 68 mmol) and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were removed by evaporation. A solid was precipitated with ether, collected by filtration and air dried to yield the title compound as a brown solid (2.25 g, 53%); NMR 1.43 (d, 6H), 2.95 (m, 6H), 3.20 (s, 3H), 4.46 (s, 2H), 5.00 (m, 1H), 5.56 (d, 1H), 7.55 (m, 2H); m/z 252.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[N:15]([CH:21]3[CH2:23][CH2:22]3)[CH2:14]4)[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1>>[CH:21]1([N:15]2[CH2:14][C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:10]4[C:5]5[C:6](=[N:7][C:2]([C:34]6[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=6)=[CH:3][CH:4]=5)[N:8]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:9]=4)[CH:12]=3)[C:16]2=[O:20])[CH2:23][CH2:22]1
Reactant: O=C1c2ccc(-c3nn(C4CCCCO4)c4nc(Cl)ccc34)cc2CN1C1CC1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cc(OC)cc(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 72, Step 4 starting from 5-[6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (M+H)+=511.2.
Reaction SMILES: Br[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:21]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]1>N1C=CC=CC=1>[C:15]1([C:2]2([O:27][CH2:26][C@H:25]3[O:28][C@@H:21]([N:29]4[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]4=[O:31])[CH2:22][C@@H:23]3[OH:24])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
770 mg (2.4 mmol) of 9-bromo-9-phenylfluorene were added to a solution of 242 mg (1 mmol) of thymidine in 10 ml of pyridine, and the resulting mixture was stirred at 100° C. for 8 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in 100 ml of methylene chloride. The solution was washed with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 30 g of silica gel (230-400 mesh), using methylene chloride containing from 1 to 3% by volume of methanol as the eluent, to give 194.2 mg (yield 37%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)cc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2cccnc21
Yield: 71.5 %

Procedure:
A solution of 103 mg of 2-hydroxymethyl-1-methyl-7-azaindole (prepared as described in Preparation 81), 346 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 166 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine in 3 ml of tetrahydrofuran was stirred at room temperature for 15 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 5:1 to 4:1 by volume as the eluent, to give 277 mg of the title compound having Rf=0.41 (on silica gel thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent).