Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=2[O:21][CH3:22])[CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-].Cl>CC#N>[CH3:22][O:21][C:12]1[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc(-c2cccc(C(=O)O)c2)c(OC)c1OC
Yield: 72.7 %

Procedure:
Dissolve 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) (566 mg, 1.87 mmol) in MeCN (19.0 mL) at rt and add 1M aqu LiOH (9.36 mL, 9.36 mmol). Stir reaction mixture overnight at rt. Quench reaction mixture (cooling bath) with 1M aqu. HCl (to get pH ca. 3). Extract the mixture with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Recrystallize crude product from EtOAc/CyH 1+3 to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid (34) as a white solid (392 mg, 72%). 1H NMR (400 MHz, CD3OD: 3.68 (s, 3H); 3.93 (br.s, 6H); 6.92 (d, 1H, J=8.6 Hz); 7.11 (d, 1H, J=8.6 Hz); 7.54 (t, 1H, J=7.7 Hz); 7.75 (d, 1H, J=7.6 Hz); 8.01 (d, 1H, J=7.8 Hz); 8.18 (br.s 1H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([NH:17][CH2:18]C=O)[CH:9]=[C:8]([C:21]([O:23]CC)=[O:22])[C:7]2=[O:26].C(O)(=O)C>C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[F:14])[N:10]([NH:17][CH3:18])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(NCC=O)c2c(OC)c(F)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
4.5 ml (0.0045 mole) of a 1N aqueous solution of sodium hydroxide were added to a solution of the whole (0.0015 mole) of the ethyl 6,7-difluoro-1-(N-formylmethylamino)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XVII, R10 =methyl) [prepared as described in Step (D3) above] dissolved in 10 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. At the end of this time, addition of acetic acid gave rise to crystals, which were collected by filtration to give 0.35 g of 6,7-difluoro-8-methoxy-1-(methylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIb, R10 =methyl) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(NCC)C>C1(C)C=CC=CC=1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]2[NH:12][N:11]=[N:10][N:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: Cc1ccc(-c2nnn[nH]2)cc1

Procedure:
In an environment of nitrogen, a mixture of p-tolunitrile (35.15 g, 300 mmol.), sodium azide (29.25 g, 450 mmol.), diethylamine hydrochloride (49.32 g, 450 mmol), and toluene (500 mL) was refluxed for 12 hours. After it was allowed to cool down, the beige suspension obtained was extracted with water (3×500 mL). Concentrated HCl was then drop-added into the water extracts to reach a pH value of around 3. The resulting white precipitates were filtered and dried in a vacuum oven all night. 5-(p-Tolyl)-1H-tetrazole in a form of white crystals (43.25 g, 90.0%) was obtained and used for the next step without any further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[S:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: OB(O)c1ccc(Cl)s1
Product: CN(C(=O)Oc1ccc(-c2ccc(Cl)s2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 5-chloro-2-thiopheneboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (53%, pink crystals).
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:13]([CH3:14])[O:12][C:11](=[O:15])[C@@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:8][CH2:7][C@@H:6]1[OH:24])[CH2:2][CH2:3][CH3:4].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([O:24][C@H:6]1[CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[C:11](=[O:15])[O:12][C@@H:13]([CH3:14])[C@@H:5]1[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1O
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@@H]1OC(=O)C(C)C
Temperature: 50 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-8-butyl-7-hydroxy-9-methyl-2-oxooxonan-3-yl)carbamate (0.405 g, 1.179 mmol) in pyridine (3.4 mL) was added DMAP (0.029 g, 0.236 mmol) followed by the slow addition of isobutyryl chloride (0.247 ml, 2.36 mmol) at room temperature. The reaction was warmed to 50° C. and stirred for 3 h, at which point additional isobutyryl chloride (0.247 ml, 2.36 mmol) was added. The reaction was stirred at 50° C. for an additional 14 h, cooled to room temperature, quenched with sat. aq. NH4Cl (5 ml), and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered, and concentrated to dryness. The crude residue was purified by flash chromatography (SiO2; EtOAc/hexanes) to give the title compound (0.274 g, 0.663 mmol, 56%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.15 (d, J=8.3 Hz, 1H), 4.91-4.84 (m, 1H), 4.79 (dq, J=10.0, 6.3 Hz, 1H), 4.27-4.16 (m, 1H), 2.60-2.44 (m, 1H), 2.23 (dt, J=13.8, 7.1 Hz, 1H), 2.15-1.99 (m, 3H), 1.73 (tdd, J=13.0, 7.3, 2.3 Hz, 1H), 1.57-1.46 (m, 1H), 1.44 (s, 9H), 1.34 (d, J=6.4 Hz, 4H), 1.33-1.19 (m, 5H), 1.18-1.12 (m, 6H), 1.04-0.94 (m, 1H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.41, 172.91, 154.98, 79.76, 74.44, 73.12, 52.42, 45.44, 34.24, 33.73, 33.32, 30.88, 28.29, 27.38, 23.25, 19.19, 19.03, 18.88, 18.79, 18.02, 13.82; ESIMS m/z 436 ([M+Na]+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1>[CH3:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of 6-nitro-1H-indole (100 mg, 0.62 mmol) and 18-Crown-6 (180 mg, 0.68 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was slowly added potassium tert-butoxide (76 mg, 0.68 mmol) followed by methyl iodide (42 μL, 0.68 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 91 mg (84%) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][N:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: O=Cc1ccnc2cccnc12
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5cccnc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1,5-naphthyridine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 9.09-9.08 (m, 1H), 8.95-8.87 (m, 1H), 8.44-8.39 (m, 1H), 8.00 (s, 1H), 7.73-7.70 (m, 1H), 7.67-7.64 (m, 1H), 5.00-4.96 (m, 1H), 4.56-4.53 (m, 1H), 4.33-4.29 (m, 1H), 3.34 (t, J=8.3 Hz, 1H), 3.19 (d, J=9.5 Hz, 1H), 2.91-2.82 (m, 2H), 2.47-2.43 (m, 1H), 2.12 (t, J=8.3 Hz, 1H), 1.48 (dd, J=9.9. 6.6 Hz, 6H), 1.18 (d, J=7.1 Hz, 3H). MS: (M+H m/z=404.2).
Reaction SMILES: [Li+].[OH-].[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1>O.C1COCC1>[CH3:3][C@H:4]1[C:12]2[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(-c2ncnc3c2[C@H](C)CC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)O)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of LiOH (64 mg, 2.68 mmol) in H2O (10 mL) was added to a solution of (R)-methyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoate (359 mg, 1.34 mmol) in THF (6 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred overnight. The volatile solvent was removed in vacuo. The aqueous layer was acidified with 1N HCl to a pH of 3. A solid precipitated, and was collected by filtration, washed with ether, and dried in vacuo to give (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid as a solid (306 mg, 90%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:33])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(=O)N(C)C3=O)nc2)CC1
Yield: 31.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (161 mg) described in Preparation Example 144 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (55 mg) was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][CH2:6][C:5]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=[CH:13][CH:12]=3.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:5]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[C:4]1=[O:3])=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)CCn2c(cc3ccccc32)C1=O
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1.3 g of sodium hydride were added over 0.5 hour to a stirred, ice-cold solution of 12.85 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 200 ml of DMF and the mixture was stirred for a further 0.5 hour. A solution of 9.2 g of ethyl bromoacetate in 50 ml of DMF was added dropwise to the cooled mixture. After a further 3 hours at room temperature the mixture was poured into 1.5 l of water and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated to give 16.3 g of ethyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.O>C(O)C>[CH:19]1([CH2:18][O:10][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: OCc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(OCC2CC2)c(F)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a suspension of 2-fluoro-4-(hydroxymethyl)phenol (1.08 g, 7.61 mmol) and potassium carbonate (2.10 g, 15.2 mmol) in ethanol (15 mL) was added bromomethylcyclopropane (1.54 g, 11.4 mmol), and the mixture was stirred at 70° C. for 4 hr. Water was added thereto, and the mixture was extracted twice with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to hexane:ethyl acetate=3:2) to give the title compound (777 mg, yield 52%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[CH2:22][CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCc2ccccc2C1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.132 g, 0.50 mmol) and 1,2,3,4-tetrahydro-isoquinoline (0.127 mL, 1.0 mmol) gives the title compound.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:40]=[C:30]2[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]2[N:28]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:40]=[C:30]4[N:31]=[CH:32][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:34][N:29]4[N:28]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: CCOC(=O)c1cnc2nc(S)nn2c1
Product: CCOC(=O)c1cnc2nc(SC3=C(O)CC(CCc4ccc(OC)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and ethyl 2-mercapto[1,2,4]triazolo-[1,5-a]pyrimidine-6-carboxylate was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[OH-].[Na+]>>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:5]([CH3:17])([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-methylpyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (370 mg, 1.52 mmol) in IMS (5 mL) was added a 1M aqueous solution of sodium hydroxide (2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and a 0.1M aqueous solution of HCl. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product as a white solid (348 mg, 100%). 1H NMR (400 MHz, CHCl3-d): δ 3.85-3.75 (m, 1 H); 3.52-3.41 (m, 2 H); 3.27-3.15 (m, 1 H); 2.39-2.30 (m, 1 H); 1.83-1.74 (m, 1 H); 1.51-1.40 (m, 9 H); 1.38 (s, 3 H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][N:18]([CH3:19])[C:8](=[O:10])[CH3:9])=[CH:15][CH:14]=1
Reactant: CNCc1ccc(Br)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)Cc1ccc(Br)cc1
Reaction time: 0.17 h

Procedure:
A solution of triethylamine (0.22 ml, 1.6 mmol) in dichloromethane (10 ml) was treated with acetyl chloride (0.08 ml, 1.10 mmol), followed by 4-bromo-N-methylbenzylamine (210 mg, 1.05 mmol). This mixture was then stirred under an atmosphere of argon for 10 minutes. The reaction mixture was washed twice with water and the organic layer was separated and dried over sodium sulphate, and the solvent removed via rotary evaporation to give a yellow oil which was purified on a 5 g sep-pak column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]2=[O:22].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 63.7 %

Procedure:
A mixture of 1.70 g of ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, 30 ml of concentrated hydrochloric acid, and 60 ml of acetic acid was heated under reflux for 1.5 hours. After allowing to cool, water was added to the reaction mixture. The precipitated crystals were collected by filtration, washed with water and ethanol, and dried. Recrystallization from a mixed solvent of ethanol and chloroform yielded 990 mg of the titled compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([O:36]CC3C=CC=CC=3)[CH:33]=[CH:32][C:31]=2[O:44]CC2C=CC=CC=2)[CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][C:20]([CH3:28])([CH3:27])[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=2[OH:44])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([CH3:27])([CH3:28])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC1(Cc2cc(OCc3ccccc3)ccc2OCc2ccccc2)COCCOCC(C)(C)COCCOC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC1(Cc2cc(O)ccc2O)COCCOCC(C)(C)COCCOC1
Yield: 108 %

Procedure:
A solution of 15.8 g (22.5 mmol) of Compound 5 in 20 mL of ethyl acetate and 20 mL of methanol was mixed with 0.4 g of palladium-on-carbon in a parr flask under a nitrogen atmosphere. The mixture was reacted at 50-60° C. under 50 psi H2 for 4 hours. After cooling, the product was filtered through Celite diatomaceous earth and the solvent removed to yield 12.7 g of impure product (Compound 6).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O>O1CCOCC1.C(OCC)(=O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Add thioacetamide (0.09 g, 1.2 mmol) to a solution of 2-bromoacetophenone (0.2 g, 1.0 mmol) in 30 mL dioxane. Stir at room temperature for 4 hours, dilute with ethyl acetate, wash sequentially with aqueous sodium carbonate (3×15 mL) and water (3×20 mL). Dry the organic phase over sodium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with hexane containing 10% ethyl acetate to provide the desired compound in 78% yield. MS(ES+): m/z=176.1 (M+H)+
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=O)C.[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N>C(#N)C>[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Agent: N
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in WO01/66099; 10.0 g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6.05 g, 41.6 mmole) and hydrogen chloride (4.0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 1N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as a white solid (12.1 g, 95%); 1H NMR Spectrum: (DMSOd6) 3.95 (s, 3H); 7.18 (s, 1H); 7.20-7.25 (m, 1H); 7.39-7.44 (m, 1H); 7.47-7.52 (m, 1H); 7.65 (s, 1H); 8.31 (s, 1H); 9.45 (br.s, 1H); Mass Spectrum: (M+H)+ 320.
Reaction SMILES: N1C=CN=C1.[CH3:6][P:7](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[C:25]([C:33]2[N:34]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:37][CH:36]=3)=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][P:7]([CH3:6])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:8])=[CH:29][CH:30]=2)[C:25]([C:33]2[N:34]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:35]3[C:40]([CH:41]=2)=[CH:39][C:38]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:37][CH:36]=3)=[N:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(O)ccc21
Reactant: CP(=O)(Cl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OP(C)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 31.4 %

Procedure:
16 mg of imidazole and 40.5 mg of methylphenylphosphinic chloride are added to a solution of 27 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-5-hydroxyindazole-1-carboxylic acid tert-butyl ester in 2 ml of dichloromethane. The solution obtained is stirred at ambient temperature. After stirring for 15 hours, a further 16 mg of imidazole and 40.5 mg of methylphenylphosphinic chloride are added and the mixture is stirred at ambient temperature for another 3½ hours in order for the reaction to be complete. The reaction mixture is then filtered and evaporated under reduced pressure in a rotary evaporator. The residue obtained is purified by LC/MS to obtain 10.5 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-5-(methylphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester.