Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[CH:7]([N:10]1[C:18]2[C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][C:16]=3[CH2:15][CH2:14][C:13]=2[C:12]([C:31]([OH:33])=[O:32])=[N:11]1)[CH2:8][CH3:9])[CH3:2].[OH-].[Na+:38]>O>[Na+:38].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[CH:7]([N:10]1[C:18]2[C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][C:16]=3[CH2:15][CH2:14][C:13]=2[C:12]([C:31]([O-:33])=[O:32])=[N:11]1)[CH2:8][CH3:9])[CH3:2]
Reactant: CCOc1cccc(C(CC)n2nc(C(=O)O)c3c2-c2ccc(OCc4cncnc4)cc2CC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cccc(C(CC)n2nc(C(=O)[O-])c3c2-c2ccc(OCc4cncnc4)cc2CC3)c1
Yield: 80 %

Procedure:
The 4,5-dihydro-1-(3-ethoxy-α-ethylbenzyl)-7-(5-pyrimidinylmethoxy)-[1H]-benz[g]indazole-3-carboxylic acid (600 mg, 1.23 m mol) obtained in Example 34 was suspended in water (20 ml) and dissolved therein by the addition of 1 N sodium hydroxide (2 ml). This solution was subjected to column chromatography using a CHP 20P resin (20 ml; manufactured by Mitsubishi Chemical Co., Ltd.), and eluted successively with water and 50% ethanol-water. After the 50% ethanol-water fraction was concentrated under reduced pressure, the residue was dissolved in water (30 ml) and this solution was concentrated again under reduced pressure. Thereafter, the residue was dissolved in water (15 ml) and freeze-dried to obtain the desired compound (500 mg, 80%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:37]([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH:26]([CH3:37])[CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 120 °C
Yield: 73.9 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.250 g, 0.485 mmol, see: Example 1) and K2CO3 (0.250 g, 1.809 mmol) in isopropanol (10 mL) was heated at 120° C. for 40 min with microwave irradiation. The reaction mixture was concentrated to dryness, was stirred in water (10 mL), filtered, washed, and dried in vacuo to provide N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (190 mg, 74.0% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1 H), 8.31 (m, 2 H), 7.87 (d, J=7.8 Hz, 1 H), 7.51-7.48 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 7.17 (d, J=2.3 Hz, 1 H), 7.04 (dd, J=5.8, 2.3 Hz, 1 H), 6.55 (d, J=8.0 Hz, 1 H), 4.85 (m, 1 H), 1.31 (d, J=6.0 Hz, 6 H); MS (ESI) m/z: 530.1(M+H+).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C1(C)C(C)=CC=CC=1>>[Cl:10][C:9]1[C:4]([F:1])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and stirrer, 139 g (2.4 mol) of potassium fluoride were introduced at 120° C. into the melt of 576 g (3.0 mol) of 2,3-dichloronitrobenzene. Subsequently, 20 g (0.19 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 60 mbar and heating to 150° C. After the xylene had been distilled off, the distillation bridge was replaced by a reflux condenser, the reaction suspension was heated to 190° C. and stirred for 6 hours at this temperature. Amount of 3-chloro-2-fluoronitrobenzene formed: 0.5 GC area-% after 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH:24]1[CH2:28][CH2:27][N:26]([C:29](=O)[CH2:30][CH3:31])[CH2:25]1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH:24]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH3:31])[CH2:25]1
Reactant: CCC(=O)N1CCC(c2cc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)ccc2OC)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN1CCC(c2cc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)ccc2OC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
N-[4-Methoxy-3-(1-propionyl-pyrrolidin-3-yl)-phenyl]-3-trifluoromethoxy-benzenesulfonamide (0.19 g, 0.4 mmol) were dissolved in 15 ml tetrahydrofurane and 2 ml 1 M boranetetrahydrofuran complex in tetrahydrofurane was added dropwise. The reaction mixture was heated to reflux for 30 minutes, 2 ml of 2 N aqueous hydrochloric acid was added and the mixture was refluxed again for 3 h. After stirring for 16 h at room temperature, the solvent was evaporated, the residue was treated with water and the pH was adjusted to alkaline pH with 1 N aqueous NaOH. The aqueous layer was extracted twice with diethylether, the combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated. The crude product was chromatographed on a chromabond column using 0-5% dichloromethane/methanol as eluent, to yield 0.077 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[C:22]4[S:29][C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=5)=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[C:22]4[S:29][C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH2:34][NH:1][CH2:2][CH2:3][CH2:4][N:5]6[CH2:9][CH2:8][CH2:7][C:6]6=[O:10])=[CH:32][CH:31]=5)=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCCN1CCCC1=O
Product: O=C1CCCN1CCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 1-(3-amino-propyl)-pyrrolidin-2-one and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d)pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 139-146° C.; LC-MS: 497 (MH+); HPLC RT: 4.01 minutes.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:3][C@H:4]([OH:41])[C@@H:5]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:49][O:50][C:51]([NH:53][C@@H:54]([C:58]([CH3:61])([CH3:60])[CH3:59])[C:55](O)=[O:56])=[O:52].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:42]([C@H:2]([NH:1][C:55]([C@@H:54]([NH:53][C:51](=[O:52])[O:50][CH3:49])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:3][C@H:4]([OH:41])[C@@H:5]([NH:19][C:20](=[O:40])[C@@H:21]([N:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:27]1=[O:39])[C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:11][CH:12]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccc(-c4ccccn4)cc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
A solution containing the product from Example 132B (0.023 mmol) in THF (0.25 mL) were added the product from Example 1F (0.005 g, 0.026 mmol), DEPBT (0.010 g, 0.033 mmol), and N,N-diisopropylethylamine (0.020 mL, 0.115 mmol), stirred at 25° C. for 16 hours, and partitioned between chloroform and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and concentrated. The product was purified by chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the product. The product was re-purified by preparative TLC eluting with 5% methanol in ethyl acetate to give the title compound (0.002 g, 11% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (s, 9 H), 0.91 (s, 9 H), 1.25 (m, 1 H), 1.52 (m, 2 H), 2.41 (m, 1 H), 2.43 (s, 3 H), 2.74 (m, 3H), 2.97 (q, J=9.2 Hz, 1 H), 3.24 (m, 1 H), 3.54 (s, 3 H), 3.66 (m, 1 H), 3.82 (d, J=9.9 Hz, 2 H), 4.09 (s, 1 H), 4.17 (m, 1 H), 4.25 (d, J=16 Hz, 1 H), 4.35 (d, J=16 Hz, 1 H), 4.53 (d, J=7.4 Hz, 1 H), 6.63 (d, J=9.9 Hz, 1 H), 7.11 (m, 8 H), 7.21 (d, J=8.09 Hz, 2 H), 7.51 (d, J=8.56 Hz, 1 H), 7.62 (t, J=7.7 Hz, 1 H), 7.75 (m, 2H), 7.83 (d, J=8.09 Hz, 1 H), 8.60 (d, J=4.1 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].Cl[C:38]1C=C(NC2C=CC(F)=CC=2F)C=C[C:39]=1C(C1C=C(C2N=NN(CC(O)=O)C=2)C=CC=1C)=O.N1CCCC1>>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([N:21]3[CH2:39][CH2:38][CH2:23][CH2:22]3)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Solvent: C1CCNC1
Product: Cc1ccc(-c2cn(CC(=O)N3CCCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.12 mmol) and pyrolidine (0.12 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 5:95 as the eluent to afford the title compound as almost yellow syrup.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:10]=1.[2H]C([2H])([2H])C#N.[2H]O[2H]>>[NH2:1][C@@H:2]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:3][NH:4][C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:10]=1
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(N2Cc3ccccc3C2=O)c1=O
Agent: [2H]C([2H])([2H])C#N
Agent: [2H]O[2H]
Product: Cn1c(NC[C@@H](N)CC2CCCCC2)nc(-c2ccncc2)c(N2Cc3ccccc3C2=O)c1=O

Procedure:
The compound was prepared similar to that of 2-[2-(2 (S)-Amino-3-phenyl-propylamino)-1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-5-yl]-2,3-dihydro-isoindol-1-one (Example 12). M+1=473. NMR H1 (CD3CN/D2O) m (2H, 0.85 ppm), m (3H, 1.15 ppm), m (8H, 1.4–1.7 ppm), s (3H, 3.4 ppm), m (2H, 3.5 ppm), m (1H, 3.7 ppm), t (1H, 4.45 ppm), dd (1H, 4.95 ppm), t (1H, 7.55 ppm), t (1H, 7.6 ppm), m (2H, 7.7 ppm), d (2H, 8.1 ppm), d (2H, 8.7 ppm).
Reaction SMILES: Cl.C[O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23](O)=[O:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].O.[OH-].[Li+]>C(Cl)Cl>[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]([NH:16][C:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][C:6]([C:4]([OH:3])=[O:5])([CH2:15]3)[CH2:7]1)[CH2:14]2)=[O:24]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(O)c1cnccn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NC12CC3CC(C1)CC(C(=O)O)(C3)C2)c1cnccn1
Yield: 94.4 %

Procedure:
To a round bottom flask was added 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (7.00 g, 28.5 mmol), 2-pyrazinecarboxylic acid (3.71 g, 29.9 mmol) and methylene chloride (200 mL). The mixture was stirred vigorously and treated with PyBOP® (15.6 g, 29.9 mmol) followed by triethylamine (9.9 mL, 71 mmol), and then stirred at room temperature for 16 hours. To the reaction was added saturated aqueous sodium bicarbonate (200 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 1-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then dissolved in tetrahydrofuran (200 mL) and water (200 mL) was added. To the biphasic mixture was added lithium hydroxide monohydrate (5.38 g, 128 mmol), and the resultant mixture stirred vigorously at room temperature for 22 hours. Most of the volatiles were removed under reduced pressure and the resulting aqueous solution was transferred to a 500-mL separatory funnel and washed with methylene chloride (3×150 mL). The aqueous layer was diluted with water (200 mL) and the pH was adjusted to about 3-4 by adding solid citric acid monohydrate. A voluminous white precipitate appeared that was filtered, washed with water and dried under high vacuum at 50° C. to afford 8.11 g (95%) of the title compound, 3-[(pyrazine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a white solid. 1H NMR (300 MHz, CDCl3) δ 11.14-10.07 (br s, 1H), 9.38 (d, J=1.5 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.50 (dd, J=2.4, 1.5 Hz, 1H), 7.68 (br s, 1H), 2.35-2.25 (m, 4H), 2.23-2.08 (m, 4H), 2.00-1.86 (m, 4H), 1.81-1.64 (m, 2H). ESI-MS m/z: 301.9 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:36])[NH:12][CH2:13][C:14]([N:16]([CH2:23][C:24](=[O:35])[N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:7]=[CH:8][CH:9]=1)[CH3:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:36])[NH:12][CH2:13][C:14]([N:16]([CH2:23][C:24](=[O:35])[N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCc3ccccc32)c2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCc3ccccc32)c2ccccc2)c1
Yield: 37.7 %

Procedure:
2.3 g of manganese dioxide are added in 2 portions at a 20-hour interval to a solution of 0.8 g of (RS)-2-{3-[3-(1-hydroxyethyl)phenyl]ureido}-N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenylacetamide in 50 cm3 of methylene chloride. The mixture is stirred at a temperature close to 25° C for 70 hours. The insoluble product is separated off by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diisopropyl ether, 0.3 g of 2-[3-(3-acetylphenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenylacetamide melting at 130° C is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([OH:39])=[CH:32]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].C(Cl)Cl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][C:33]([OH:39])=[CH:32]3)=[CH:4][N:3]=1
Reactant: Oc1cnc2ccc(Br)cc2c1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(O)cc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a microwave vial (5 mL) was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.129 g, 0.312 mmol), 6-bromoquinolin-3-ol (Li et. Al, Bioorganic & Medicinal Chemistry Letters (2006), 16(7), 2000-2007) (0.0703 g, 0.314 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0128 g, 0.0156 mmol) and potassium carbonate (2.0 M, 0.390 mL, 0.781 mmol) in 1,4-dioxane (3 mL). The mixture was degassed by bubbling nitrogen through for 10 min. The tube was irradiated with microwave at 100° C. for 10 min. The reaction mixture was cooled to RT then partitioned between water (10 mL) and EtOAc (10 mL). The product went into aqueous almost exclusively. The aqueous phase was passed through BE-SCX column (Varian, Palo Alto, Calif., 10 gm) then eluted with MeOH. MeOH fraction contains the product. MeOH was evaporated and yielded a brown solid (0.0846 g) as the desired product. m/z: calc'd for C20H13ClFN3O3S: 429.0; found 430.0 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.21-7.35 (m, 2 H), 7.52-7.65 (m, 2 H), 7.74-7.86 (m, 3 H), 7.89 (d, J=1.8 Hz, 1 H), 7.96 (d, J=8.6 Hz, 1 H), 8.03-8.15 (m, 1 H), 8.58 (d, J=2.8 Hz, 1 H), 10.40 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:18])[CH:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=4[F:45])=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate (450 mg, 0.72 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as grey solid. Yield: 320 mg, 85%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15][C:16]([C:18]2([NH:33]C(=O)OC(C)(C)C)[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:33][C:18]1([C:16]([NH:15][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])=[O:17])[CH2:19][CH2:20][N:21]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:22][CH2:23]1
Reactant: CN(C)CCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 1.01 mL, 4.05 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 34) (0.045 g, 0.08 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 16 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(dimethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.034 g, 92%) as a colourless gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccnc(-c2cccs2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(c2ccnc(-c3cccs3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-2-yl-pyridine (98 mg, 0.5 mmol), 1-methylpiperazine (200 mg, 1 mmol), 2-propanol (1.0 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield a reside. The residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>C(Cl)Cl>[CH:9]([N:22]1[CH2:25][CH:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
tert-Butyldimethylsilyl chloride (1.524 g, 10.11 mmol) was added to 1-benzhydrylazetidin-3-ol (CAS no. 18621-17-5) (2.2 g, 9.19 mmol) and imidazole (1.565 g, 22.98 mmol) in DCM (46.0 mL) at r.t. under nitrogen. The resulting solution was stirred at r.t. for 3 hours. The reaction mixture was quenched with water, poured onto a phase separator and evaporated to afford the product (3.66 g, 113%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.85 (9H, s), 2.81 (2H, s), 3.52 (2H, s), 4.35 (1H, s), 4.40-4.49 (1H, m), 7.08-7.43 (10H, m); m/z (ES+) (M+H)+=354.55; HPLC tR=2.04 min.