Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[O-]CC.[Na+].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>C(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][S:5][CH2:4][CH2:3][NH2:2]
Reactant: NCCS
Reactant: COc1ccccc1CCl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1CSCCN
Reaction time: 8 h
Yield: 36.7 %

Procedure:
Cysteamine hydrochloride (2.12 g) was added to a solution of sodium ethoxide (from 0.87 g sodium) in ethanol (50 ml) stirred under nitrogen in an ice-bath. 2-Methoxybenzyl chloride (2.93 g) was added dropwise and the mixture was stirred in an ice-bath for 0.5 hr. and allowed to stand at room temperature overnight. The mixture was evaporated to dryness. Water was added to the residue and the mixture was extracted at pH 3 with chloroform (discarded), adjusted to pH 13 and extracted a second time with chloroform. This second extract was purified by elution from silica gel with chloroform/methanolic ammonia (50:1) to give 2-(2-methoxybenzylthio)ethylamine (1.35 g) as an oil which was treated with hydrogen chloride in ethanol to give the hydrochloride m.p. 128°-30° (ethanol/ether).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[Si:19]([O:26][CH2:27][C@H:28]([OH:34])[CH2:29][O:30][CH:31]([CH3:33])[CH3:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[H-].[Na+]>C1COCC1>[Si:19]([O:26][CH2:27][C@@H:28]([CH2:29][O:30][CH:31]([CH3:33])[CH3:32])[O:34][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.46 g), (2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-isopropoxypropan-2-ol (product of step (0.66 g), THF (5 mL) and 60% sodium hydride (80 mg), to give the subtitle compound as a colourless oil. Yield: 0.56 g
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([CH2:49][CH2:50][CH2:51][O:52][C:53](=[O:55])[CH3:54])[C:20]([O:22][C@H:23]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)[CH:35]=3)[CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=3[Cl:33])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCOCC1>C(Cl)Cl>[C:53]([O:52][CH2:51][CH2:50][CH2:49][C@@H:19]([NH2:18])[C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:26]([Cl:33])=[CH:27][N+:28]([O-:32])=[CH:29][C:30]=1[Cl:31])=[O:21])(=[O:55])[CH3:54]
Reactant: CC(=O)OCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC(=O)OCCC[C@@H](N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 4-((S)-2-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-acetoxypentanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-ethyl)-3,5-dichloropyridine 1-oxide (284 mg, 0.355 mmol) dissolved in DCM (5.7 ml), morpholine (615 μl, 7.10 mmol) was added. The mixture was stirred at RT for 48 hours. The mixture was then diluted with DCM and washed twice with water. The organic phase was dried over Na2SO4 and the solvent was evaporated, to yield 205 mg of the title compound.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N+:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26](=[O:29])[C:27]#[CH:28]>O1CCCC1>[C:26]([C:27]1[CH:28]=[C:11]([C:10](=[O:18])[C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=2)[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)(=[O:29])[CH3:25]
Reactant: N#Cc1ccc(C(=O)C[n+]2ccccc2)cc1
Reactant: C#CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)c2ccc(C#N)cc2)n2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A slurry of 1-(2-(4-cyano-phenyl)-2-oxo-ethyl)-pyridinium bromide (11) (4.04 grams, 13.2 mmol) and potassium carbonate (2.21 grams, 16.0 mmol) in tetrahydrofuran (250 mL) was stirred at room temperature for 10 minutes. To it was added 3-butyn-2-one (1.4 mL, 16.0 mmol), and the reaction mixture was kept stirring at room temperature for 6 hours. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was subjected to column chromatographic purification on silica gel using 3:1 hexane and ethyl acetate (Rf 0.2) to afford 1-acetyl-3-(4-cyanobenzoyl)indolizine (12) as a yellow solid (2.55 grams, 72%). 1H NMR (CDCl3) δ 2.56 (s, 3H), 7.23 (m, 1H), 7.62 (m, 2H), 7.90 (m, 4H), 8.72 (d, J=9.0, 1H), 10.02 (d, J=6.6, 1H); ESMS calcd (C18H12N2O2): 288.1. found: 289.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[Cl:18][C:19]([Cl:33])([Cl:32])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.O>CN(C=O)C>[Cl:18][C:19]([Cl:32])([Cl:33])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Cesium carbonate (1.69 g, 5.20 mmol) was added to a mixture of 3-mercapto-phenylacetic acid (0.73 g, 4.33 mmol) and 2-bromomethyl-benzoic acid 2,2,2-trichloro-ethyl ester (1.50 g, 4.33 mmol) in DMF (25 mL). The mixture was stirred for 1 h at rt. Water was added and the mixture was washed with diethyl ether. The aqueous phase was made acidic (pH5-3) with 2M HCl and thereafter extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and concentrated to give the titled compound (1.88 g, 100%); 1H NMR (400 MHz, CDCl3): δ 3.50 (s, 2H), 4.46 (s, 2H), 4.88 (s, 2H), 7.01-7.08 (m, 1H), 7.10-7.16 (m, 4H), 7.22-7.35 (m, 2H), 8.00 (d, 1H); Mass spectrum: M−H+ 432.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[O:14][C:6]=3[C:5]=2[CH:4]=1.Cl.Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:24][CH:23]=1>>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:8]2[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[C:7]2=3)=[CH:35][CH:34]=1)[CH3:33]
Reactant: COc1ccc2[nH]c3c4ccccc4oc3c2c1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4ccccc4c32)cc1

Procedure:
Following the procedure described in Example 102, using 3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (405 mg, 1.517 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt as a starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:21]1[N:22]([CH3:32])[C:23](=[O:31])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21]2[N:22]([CH3:32])[C:23](=[O:31])[CH:24]=[CH:25][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[C:4]([F:9])[CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a white crystalline solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:55]([CH3:54])(=[O:57])=[O:56])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 118 (43 mg, 0.07 mmol) in DCM (1.5 mL) was added DIPEA (49 μL, 0.18 mmol) followed by methanesulfonyl chloride (11 μL, 0.11 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.38 min, m/z 679 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)(=[O:23])=[O:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:27]3[CH2:26][C@@H:25]4[CH2:30][C@H:28]3[CH2:29][N:24]4[S:21]([CH3:20])(=[O:23])=[O:22])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2C[C@@H]3C[C@H]2CN3S(C)(=O)=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 17 h
Yield: 97.8 %

Procedure:
A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (227 mg, 0.81 mmol), (1S,4S)-2-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane (170 mg, 0.97 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (12 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (255 mg, 1.20 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 98:2) to afford the title compound as a white solid (350 mg, 98%). LCMS (Method H): RT=2.51 min, M+H+=442.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl.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.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in CH2Cl2 (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH3) m/z 379 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.N>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6](=[CH:5][CH:4]=1)[CH2:7][NH:8][CH2:9][CH:10]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(CNCC(O)c2ccc(OC)c(OC)c2)cc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Yield: 88.2 %

Procedure:
α-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (950 mg) was dissolved in 7.2 ml of trifluoroacetic acid, and after adding thereto 0.22 ml of conc. sulfuric acid under cie cooling, the reaction was allowed to react for 45 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous amminoa under ice cooling. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (chlroform-methanol28% aqueous ammonia=15:1:0.1), giving 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as oily matter.
Reaction SMILES: COC([CH2:5][NH:6][N:7]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1)=O.[OH-].[Na+].O>C(O)(=O)C>[CH3:5][NH:6][N:7]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(NCC(=O)OC)c2cc3c(cc2c1=O)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CNn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 95 °C
Reaction time: 4.5 h
Yield: 86.7 %

Procedure:
A mixture of 4.6 g (0.0132 mole) of ethyl 5,8-dihydro-5-[(methoxycarbonyl)methylamino]-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 5), 1.6 g (0.0396 mole) of sodium hydroxide and about 100 ml of water was stirred at 95° C. for 4.5 hours. The reaction mixture was cooled, acidified with 5 ml of acetic acid with stirring, and kept in a refrigerator overnight. The solid product was collected by filtration, washed with water and recrystallized from 70 ml of boiling dimethylformamide. There was obtained 3 g of 5,8-dihydro-5-(methylamino)-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid, colorless crystals, m.p. above 300° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([F:12])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Br)c(F)cc1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
5-Bromo-4-fluoro-2-hydroxybenzoic acid (I-227) (34.39 g, 0.146 mol) was dissolved in concentrated sulfuric acid (260 ml), and cooled at 0° C. At the same temperature, fuming nitric acid (d=1.52) (6.67 ml, 0.161 mol) was dropwise added with keeping the inner temperature at 0° C. or lower (about 20 minutes). After the addition, the disappearance of the starting material was confirmed by TLC, then the reaction liquid was gradually poured into ice. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated away. N-hexane was added to the residue, the crystal was ground, the suspension was stirred at room temperature for 1 hour (optionally with sonication). The crystal was washed with n-hexane, followed by filtration and drying to obtain the entitled compound (33.82 g, 83%) as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[C:9]([O:21]CC3C=CC=CC=3)[CH:8]=2)[CH2:5][N:4]=[C:3]1[NH:29][C:30]([O:32][CH3:33])=[O:31]>[Pd].C(O)C.[H][H]>[CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:21])[CH:8]=2)[CH2:5][N:4]=[C:3]1[NH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: [H][H]
Reactant: COC(=O)NC1=NCC(c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)N1C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)NC1=NCC(c2ccc(O)c(O)c2)N1C

Procedure:
This example illustrates methods according to the invention of preparing mono- and dihydroxy substituted phenyl compounds of the invention. In this example, 3.0 g. of β-methylamino-β-(3,4-dibenzyloxyphenyl)ethylamine is dissolved in 50 ml of ethanol and 2 ml of water. The solution is combined with a solution of 1.7 g of a mixture of 1-mono and 1,3-bis (methoxycarbonyl)-S-methylisothiourea in 25 ml of chloroform and allowed to stand for 8 days and then concentrated to dryness. The residue is treated with 100 ml of 0.5N hydrochloric acid and the resulting slurry is stirred vigorously in the presence of ethyl ether. Stirring is discontinued and the ether layer is removed by decantation. This process is repeated four times and the remaining aqueous slurry is then treated in the excess of saturated aqueous sodium bicarbonate solution. The product, 1-methyl-4,5-dihydro-5-(3,4-dibenzyloxyphenyl)-2-methoxycarbonylaminoimidazoline, is extracted into chloroform, the chloroform is removed and the remaining product is purified by recrystallization from 300 ml of benzene. By treating the resulting free base with a solution of 10 ml of ethanol that contains 400 mg of hydrogen chloride and then with 200 ml of ether, the hydrochloride salt is obtained. A sample of the hydrochloride salt of 1-methyl-4,5-dihydro-5-(3,4-dibenzyloxyphenyl)-2-methoxycarbonylaminoimidazole is treated according to a standard hydrogenolysis procedure using palladium-on-charcoal catalyst in ethanol and hydrogen gas at atmospheric pressure, to afford the hydrochloride salt of 1-methyl-4,5-dihydro-5-(3,4-dihydroxyphenyl)-methoxycarbonylaminoimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:29]([C:32]1[N:33]=[N:34][N:35]([CH2:37][C:38](O)=[O:39])[CH:36]=1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>>[CH3:28][C@@H:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:35]3[CH:36]=[C:32]([CH:29]([CH3:30])[CH3:31])[N:33]=[N:34]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: CC(C)c1cn(CC(=O)O)nn1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cn(CC(=O)Nc2cncc(C(=O)c3cn([C@H](C)COC4CCCCO4)c4ncncc34)c2)nn1

Procedure:
Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Preparation 36) and (4-isopropyl-1H-1,2,3-triazol-1-yl)acetic acid with DIPEA as base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:26]([C:29](Cl)=[O:30])([CH3:28])[CH3:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:29](=[O:30])[CH:26]([CH3:28])[CH3:27])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(-c2cccc3nc(N)nn23)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2cccc3nc(NC(=O)C(C)C)nn23)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the 5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.07 g, 0.291 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.12 mL, 0.874 mmol) followed by isopropanecarbonyl chloride (0.046 mL, 0.437 mmol). The reaction mixture was then allowed to warm to ambient temperature overnight. Further triethylamine (1.5 eq) and acid chloride (1.2 eq) were added to ensure complete reaction. The solvent was then removed and 3 mL of methanol-ammonia 7M was added to the crude and the mixture was stirred 6h. The solution was concentrated under reduced pressure and the crude was purified by preparatory HPLC. LCMS method: 2, RT: 4.33 min, MI: 311 [M+1]. NMR 1H (DMSO): 1.05 (d, 6H), 2.65-2.75 (m, 1H), 3.86 (s, 3H), 7.06 (d, 2H), 7.19 (d, 1H), 7.57-7.69 (m, 2H), 7.95 (d, 2H), 10.68 (brs, 1H).
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]1[C:40]([C:41]([C:43]([F:46])([F:45])[F:44])=O)=[CH:39][CH:38]=[C:37]([C:47]([F:50])([F:49])[F:48])[CH:36]=1.CCCCCC>C1COCC1>[CH3:13][O:14][CH:15]=[C:41]([C:40]1[CH:39]=[CH:38][C:37]([C:47]([F:50])([F:49])[F:48])=[CH:36][CH:35]=1)[C:43]([F:46])([F:45])[F:44]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 25.0 ml of n-butyllithium/hexane solution (1.2M solution) was added to a solution of 12.7 g of methoxymethyltriphenylphosphonium chloride in 100 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 30 minutes and at -20° C. for 30 minutes. A solution of 6.0 of 4-trifluoromethyl-α,α,α-trifluoroacetophenone in 10 ml of dry THF was slowly added to the reaction solution at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at room temperature for 14 hours. Thereafter, 150 ml of n-hexane was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with dilute HCl-ice water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and 6.1 g of the crude product (E/Z=ca. 1/1) was obtained.