Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[C:15]([CH:17]1[CH2:19][CH2:18]1)#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CC#N.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:17]1([C:15]#[C:16][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[NH2:12])[CH2:19][CH2:18]1
Reactant: C#CC1CC1
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C#CC2CC2)c(N)c1
Yield: 95.1 %

Procedure:
bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol), ethynylcyclopropane (0.7 g, 10.72 mmol), K2CO3 (1.5 g, 10.72 mmol) in CH3CN (30 ml), Pd(ACN)2Cl2 (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27 mmol) under N2 were heated at 45° C. for 3 h. EA extractive work up and preparative TLC (PE:EtOAc=5:1) gave the title compound (1.2 g).
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](O)([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:27])[CH2:8]2)(=O)C.[C:28]([NH:31][NH2:32])(=[O:30])[CH3:29]>C(O)C.Cl>[C:28]([NH:31][N:32]=[C:11]([C:12]1[C:7]([CH2:8][CH:9]([OH:10])[CH3:27])=[CH:6][CH:5]=[C:14]([O:15][CH3:16])[C:13]=1[NH:31][C:28](=[O:30])[CH3:29])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)NN
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(C)O)c(C(=NNC(C)=O)c2ccc([N+](=O)[O-])cc2)c1NC(C)=O
Yield: 86.5 %

Procedure:
To a solution of 22 (1.7 g) in 25 ml of ethanol was added acetic hydrazide (0.5 g) and 2 drops of concentrated HCl. The resulting solution was refluxed for 3 hours. The solvent was removed under reduced pressure. The residue was treated with NaHCO3, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4. Removal of the solvent gave the desired product 23 (1.25 g).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccc(Br)n1
Product: CN(C(=O)On1ccc(Br)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]([S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(Cl)nc3)sc2c1O
Reactant: Sc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2nc(-c3ccc(Sc4ccccc4)nc3)sc2c1O
Temperature: 100 °C

Procedure:
A suspension of 2-(6-chloro-pyridin-3-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester, example 92(c)(0.25 g, 0.75 mmol) and triethylamine (0.21 mL, 1.49 mmol) in thiophenol was heated at 100° C. overnight. 100 mL of chloroform was added. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to produce 49.0 mg of a light yellow solid. MS: (+) m/z 410.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[C:58]([N+:66]([O-:68])=[O:67])[CH:57]=1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:59]1[CH:60]=[CH:61][C:56]([O:55][CH3:54])=[CH:57][C:58]=1[N+:66]([O-:68])=[O:67])(=[O:63])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(OC)cc1[N+](=O)[O-])O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino)-propionic acid methyl ester (20 mg) was reacted with 4-methoxy-2-nitro-benzenesulfonyl chloride to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methoxy-2-nitro-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (5 mg) was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z): 951.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][C:23]([CH:30]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][C:23]([CH2:30][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1C(C)(C)C
Yield: 76.7 %

Procedure:
Compound 64 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16]O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 4 h

Procedure:
To a solution of (3-(hydroxyimino-methyl)-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step B (2.25 g, 5.96 mmol) in EtOH (10 mL) was added Raney Nickel (about 1 g, washed with water followed by EtOH) in 100 mL EtOH. Additional EtOH (90 mL) was required for the transfer. Ammonium hydroxide (10 mL) was added and the mixture was shaken under 45 psi of H2 for 4 hours. The catalyst was removed via filtration through Celite® and the solution was concentrated to a clear oil. Purification via flash chromatography on silica gel (96.5/3.5/0.1 to 9/1/0.1 CH2Cl2/MeOH/NH4OH) afforded the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.92 (m, 2H), 6.72 (d, 1H), 4.50 (s, 2H), 3.82 (s, 2H), 1.96 (m, 2H), 1.46 (s, 9H); MS 238 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20](O)=[O:21])[CH2:7]1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:30]=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2[N:33]=[C:20]([CH:8]3[CH2:9][CH:10]([C:12]4[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=4)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]3)[O:21][N:32]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: NC(=NO)c1ccnc(Cl)c1
Product: CCc1ccc(C2CC(c3nc(-c4ccnc(Cl)c4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 13 mg (14% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1.N1CCCCC1>C(O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11](=[O:13])/[CH:12]=[CH:23]/[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1cc(OC)cc(C(C)=O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(OC)cc(C(=O)/C=C/c2c[nH]c3ccccc23)c1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
3',5'-Dimethoxyacetophenone (1.10 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 32 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration, followed by recrystallization from ethanol to give Compound 69 (1.79 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Nc1ccc(-c2cc3ocnc3cc2Cl)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3ocnc3cc2Cl)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-6-yl)-2-pyridylamine (31) (23 mg, 0.09 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (23 μl, 0.18 mmol) followed by addition of DIEA (94 μl). The resulting brown solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (135 μl) at r.t. for 30 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 17 mg 32 as pale yellow solid. (yield: 49%).
Reaction SMILES: [C:1]1([CH2:11][N:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH2:13][CH2:14][OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:1]1([CH2:11][N:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH2:13][CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[Naphthalen-1-ylmethyl-(3-phenylisoxazol-5-yl)amino]ethanol (820 mg, 2.38 mmol) was dissolved in methylene chloride (15 ml), treated with triethylamine (592 μl, 4.25 mmol) followed by methanesulfonyl-chloride (265 μl, 3.42 mnmol) and the solution stirred at rt for 1.5 hr. The reaction was washed with 50% sodium bicarbonate (aq, 2×), water (1×), and brine (1×), dried over sodium sulfate, filtered and stripped to dryness in vacuo to give the product as a sticky, foam (1.07 gm, quantitative).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[N:8]1([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:24]3[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)[CH:3]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1

Procedure:
Tert-butyl 4-(6-aminopyrimidin-4-yl)piperazine-1-carboxylate 12-2 (0.25 g, 0.9 mmol), sodium hydride (0.072 g, 1.8 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.129 g, 0.9 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and evaporated to dryness. The residue was then treated with trifluoroacetic acid and the product was isolated from a sodium carbonate/methyene chloride partition. 1H-NMR (CD3OD): 8.47 ppm (s, 1H); 8.02 ppm (s, 1H); 6.24 ppm (s, 1H); 3.88 ppm (t, 4H); 3.27 ppm (t, 4H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH3:18][C:19]1C=CC=C(C)[C:20]=1CN1C2C(=CC=C(C(O)=O)C=2)C=C1>>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Reactant: Cc1cccc(C)c1Cn1ccc2ccc(C(=O)O)cc21
Product: C=CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (5.7 g) as a colorless oil was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate (7.5 g) obtained with the method described in the document (WO 1998/43956 A) according to the method of the process (2) of Example 66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][NH2:10].F[C:12]1[N:19]=[CH:18][CH:17]=[C:16]([I:20])[C:13]=1[CH:14]=O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:12]2=[N:19][CH:18]=[CH:17][C:16]([I:20])=[C:13]2[CH:14]=[N:10]1
Reactant: NNc1c(F)cccc1F
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1cccc(F)c1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 111.5 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added (2,6-difluorophenyl)hydrazine (431 mg, 2.99 mmol), 2-fluoro-4-iodonicotinaldehyde (750 mg, 2.99 mmol) and anhydrous NMP (4.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1.5 h. The reaction mixture was worked up according to the general procedure described in Intermediate 69A to give 1.19 g (quantitative yield) of the title compound (contains approximately 50% of the hydrazone intermediate) as thick, dark oil. LC/MS (Condition B): ret. T=3.5 min, (M+H)+ 357.91.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C(O)(=O)C.[Pd]>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 97.6 %

Procedure:
III (7.8 g, 0.0123 mole) was taken in acetic acid (80 ml) and hydrogenated in the presence of 10% Pd-C. (1 g) at 40 psi. After filtering the catalyst with the aid of celite, the solvent was removed under reduced pressure, triturated with ether, filtered, washed with ether then pet. ether and dried to obtain 6.5 g of the product (yield: 97.3%), m.p. shrinks at 127° C. and decomp. at 3 145° C. Rf3, 0.24; Rf4, 0.11 Anal. Calcd. for C25H43N5O10.1/2H2O: C 54.52, H 8.05, N 12.71%. Found: C 54.32, H 8.02, N 12.59%.
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>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>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH3:35])(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
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
Solvent: C1COCCO1
Product: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (30 mg, 0.181 mmol), (cis)-1-acetyl-6-bromo-2-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 90) (40 mg, 0.107 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was treated with potassium carbonate (45 mg, 0.326 mmol) and the resulting mixture was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave 4-[(cis)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (20 mg, 0.048 mmol, 45%)
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][C:17]3[C:22]4[C:23]([CH3:27])([CH3:26])[CH2:24][O:25][C:21]=4[C:20]([CH3:28])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)C=CC=CC=1.O.[NH2:31][NH2:32].O>O1CCOCC1>[CH3:26][C:23]1([CH3:27])[C:22]2[C:17]([O:16][C:13]3[N:12]=[CH:11][C:10]([NH:9][C:8]([NH:31][NH2:32])=[O:29])=[CH:15][CH:14]=3)=[CH:18][CH:19]=[C:20]([CH3:28])[C:21]=2[O:25][CH2:24]1
Reactant: Cc1ccc(Oc2ccc(NC(=O)Oc3ccccc3)cn2)c2c1OCC2(C)C
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(NC(=O)NN)cn2)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Phenyl{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}carbamate (Intermediate 1, 640 mg, 1.64 mmol) was dissolved in dioxane (7 mL) and hydrazine monohydrate (8.2 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature and then at 70° C. for 1 hour. Water was added and the resulting suspension was stirred for 1 hour and then filtered. The solid was collected, washed with water and dried under vacuum at 25° C. affording the title compound (340 mg) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O-])=O)=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH:15]([CH3:17])[CH3:16])[NH:5]1
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Reactant: Nc1ccc(CC(=O)[O-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Cl)c1-n1[nH]c(C(C)C)c2c(=O)nc(Cc3ccc(N)cc3)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by coloumn chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec.(CI+): 408 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:61])[CH2:21][CH2:22][C:23](=[O:60])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:31](=[O:51])[CH2:32][CH2:33][C:34](=[O:50])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:62](Cl)(=[O:72])[CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71]>>[CH2:1]([O:8][N:9]([C:20](=[O:61])[CH2:21][CH2:22][C:23](=[O:60])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:31](=[O:51])[CH2:32][CH2:33][C:34](=[O:50])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:62](=[O:72])[CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCCOCC(=O)Cl
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)COCCOCCOC
Yield: 78 %

Procedure:
11,22,33-Tris(benzyloxy)-12,15,23,26,34-pentaoxo-11,16,22,27,33-pentaaza-2,5,8,36,39,42-hexaoxatritetracontane (23) was synthesized by reacting compound (21) (3.91 g, 4.60 mmol) with 3,6,9-trioxadecanoyl chloride [Helmann, supra] (NEt3 /CH2C12) to give 4.0 g (78%) of (23): NMR δ 1.17-1.78 (m, 12 H), 2.3-2.9 (m, 8 H), 3.04-3.37 (m, 10 H), 3.4-3.8 (m, 24 H), 4.21 (s, 2 H), 4.76 (s, 2 H), 4.81 (s, 2 H), 4.88 (s, 2 H), 6.17-6.37 (m, 2 H), 7.34 (s, 15 H). Analysis: (C53H79N5O14) C, H, N.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][C:4]=1[C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.B(Br)(Br)Br.O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[OH:2][C:3]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][C:4]=1[C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(-c2ccccc2)cc(C(C)(C)C)cc1-c1cccc(C=O)n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2ccccc2)c(O)c(-c2cccc(C=O)n2)c1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
In the glovebox, 6-(2′-methoxy-3′-phenyl-5′-tert-butylphenyl)-2-formyl-pyridine (11) (4.43 g, 12.3 mmol) was dissolved in 75 mL dichloromethane and cooled to −80° C. A 20 mL dichloromethane solution of BBr3 (4.62 g, 18.5 mmol) was slowly added dropwise and the solution was left to stir at −80° C. for 1 h. After warming to room temperature, the orange solution was taken out of the glovebox and under a purge of nitrogen, ˜1 mL of water was added, causing a large amount of smoke to form. A further 5 mL of water was slowly added, followed by 30 mL of dichloromethane and another 10 mL portion of water. This was stirred for 30 minutes, neutralized with 1M Na2CO3 and the water layer separated from the organic layer. The water layer was extracted with 2×75 mL dichloromethane, the organic layers combined and washed with water (2×100 mL), dried over MgSO4, filtered and dried to give compound 12 as a yellow solid. Yield: 4.25 g (100%).