Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O>CCOC(C)=O.[Pd]>[N:17]1([C:15]([C:5]2[C:4]([NH2:1])=[CH:8][N:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:6]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(c1nn(-c2ccccc2)cc1[N+](=O)[O-])N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cn(-c2ccccc2)nc1C(=O)N1CCOCC1
Reaction time: 18 h
Yield: 91.8 %

Procedure:
To a solution of 4-[(4-nitro-1-phenyl-1H-pyrazol-3-yl)carbonyl]morpholine (376 mg; 1.24 mmol; 1.00 eq.) in AcOEt (10 mL) is added Pd/C 10% (-50% H2O) (13.24 mg; 0.12 mmol; 0.10 eq.) and under H2 Atm. (1 atm.). After 18 h, reaction mixture is filtered over a celite bed, ished with AcOEt to give 310 mg (92%) of the title compound as a purple solid. 1H NMR (DMSO): δ 7.85 (s, 1H), 7.77-7.72 (m, 2H), 7.53-7.44 (m, 2H), 7.30 (t, J=7.4 Hz, 1H), 5.14-4.90 (m, 2H), 4.31-4.14 (m, 2H), 3.73-3.58 (m, 4H), 3.43-3.23 (m, 2H). HPLC (max plot) 95.6%; Rt 2.01 min. MS (ESI+): 272.9.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1.C(O)(=O)C.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:2][C@@H:3]1[CH2:7][N:6]([CH2:35][C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=2)[CH2:5][C@H:4]1[C:8]1[NH:9][C:10](=[O:23])[C:11]2[CH:16]=[N:15][N:14]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]=2[N:13]=1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Reactant: Cc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
To a solution of 6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride (493 mg) in 1,2-dichloroethane (10 mL) was added acetic acid (174 mg), 2-methylpyrimidine-5-carbaldehyde (236 mg) and sodium triacetoxy borohydride (635 mg). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated onto silica gel and purified by CombiFlash chromatography to provide the title compound (146 mg). 400 MHz 1H NMR (CDCl3) δ 8.63 (s, 2H), 8.01 (s, 1H), 4.82-4.76 (m, 1H), 4.12-4.08 (m, 2H), 3.68 (d, J=5.0 Hz, 3H), 3.64-3.54 (m, 2H), 3.28 (t, J=8.3 Hz, 1H), 3.04 (d, J=9.9 Hz, 1H), 2.89-2.86 (m, 1H), 2.71 (s, 3H), 2.66-2.62 (m, 1H), 2.49-2.27 (m, 3H), 1.97 (t, J=7.9 Hz, 1H), 1.91-1.83 (m, 2H), 1.19 (d, J=7.05 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCC1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 4-hydroxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (148.35 mg, 0.64 mmol) was dissolved in anhydrous DCM and triethylamine (194.28 mg, 1.92 mmol, 0.27 mL) was added under argon. The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (80.64 mg, 0.70 mmol, 0.06 mL) was added via syringe. The reaction was stirred at 0° C. for 30 min and then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (2:1 hexane-ethyl acetate) Yield 172.26 mg. 1H NMR (CDCl3, 300 MHz): δ 1.49 (s, 9H), 2.32 (bs, 2H), 3.04 (s, 3H), 3.35 (s, 3H), 3.44 (d, J=6 Hz, 1H), 3.49-3.88 (m, 3H), 4.11 (bs, 1H), 5.25 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[Cl:31])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccccc1Cl
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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of ((2R)-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate, prepared in Example 3, step 1 (0.50 g, 1.1 mmol), 2-chlorophenylboronic acid (0.34 g, 2.2 mmol), potassium carbonate (0.46 g, 3.3 mmol) and lithium chloride (0.14 g, 3.3 mmol) in dioxane (3.75 mL) and water (1.25 mL) was purged with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.052 mmol) was added and the reaction mixture heated to 100° C. for 4 hours. The cooled reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M aqueous sodium hydroxide (15 mL). The organic layer was separated, washed with saturated brine (15 mL) dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 0.38 g (81%) of [(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzene sulfonate as a white solid. HRMS: calcd for C23H21ClO4S+H+, 429.09218. found (ESI, [M+H]+), 429.0924.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[OH-].[Na+]>FC(F)(F)C(O)=O.O.O=[Pt]=O>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reaction time: 96 h
Yield: 56.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtO2 (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The yellow oil was dissolved in 200 mL of H2O then made basic (pH˜11) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5×75 mL) and the combined organic layers were dried over Na2SO4 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid. MS 334 (M+H)+; 1H NMR (300 MHz, CDCl3) δ5.19 (s, 2 H); 4.49 (t, J=5.4 Hz, 2 H); 3.84 (t, J=6.6 Hz, 2 H); 3.71 (t, J=5.4 Hz, 2 H), 3.36 (t, J=5.2 Hz, 2 H); 3.51 (s, 3 H); 3.15 (t, J=6.6 Hz, 2 H); 2.95 (m, 2 H); 2.82 (m, 2 H); 2.76 (t, J=5.1 Hz, 2 H); 1.84 (m, 4 H), 1.47 (br s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:5]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 40 °C
Yield: 77.3 %

Procedure:
2-Chloro-4-nitrobenzoyl chloride (23.1 g) was added dropwise to a mixture composed of 11.8 g of monochlorobenzene and 13.3 g of aluminum chloride. The mixed solution was stirred with heating at 40° C. for 6 hr and was then added dropwise to 45 mL of warm water. Further, toluene and ethyl acetate were added to the mixed solution followed by separation and washing with sodium bicarbonate water and brine. The organic layer was concentrated under the reduced is pressure. n-Hexane was added to the residue, and the precipitated crystals were collected by filtration to give 24.0 g of (2-chloro-4-nitrophenyl)-(4′-chlorophenyl)methanone (yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@H:24]3[C@H:28]4[O:29][CH2:30][CH:31]([CH2:32][C:33]([O:35]CC)=[O:34])[C@H:27]4[O:26][CH2:25]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@H:24]3[C@H:28]4[O:29][CH2:30][CH:31]([CH2:32][C:33]([OH:35])=[O:34])[C@H:27]4[O:26][CH2:25]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
A mixture ethyl 2-[(3aR,6R,6aS)-6-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (4.4 mg, 0.0085 mmol) and 3M sodium hydroxide (2.8 uL, 0.085 mmol) in ethanol (0.5 ml) was stirred at room temperature for 20 minutes. The reaction mixture was then purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give a major and minor isomers which were lyophilized to give the title compounds. Minor isomer: LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.22 (M+H)+ (Rt 1.11/2 min); 1H NMR δ (ppm) (CD3OD): 7.88 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.56 (qt, 1H), 4.98 (t, 1H), 4.42 (d, 1H), 4.13 (dd, 2H), 4.05-3.98 (m, 3H), 3.72 (dd, 1H), 2.71 (m, 1H) and 2.44-2.33 (m, 2H). Major isomer: LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.20 (M+H)+ (Rt 1.12/2 min); 1H NMR δ (ppm) (CD3OD): 7.94 (s, 1H), 7.76 (ABq, 4H), 7.72 (d, 2H), 7.49 (dd, 2H), 7.39 (dd, 1H), 5.59 (m, 1H), 5.01 (t, 1H), 4.61 (t, 1H), 4.12 (dd, 2H), 4.08-4.00 (m, 3H), 3.53 (dd, 1H), 2.70 (dd, 1H), 2.59 (m, 1H) and 2.49 (dd, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1>CC(C)=O.ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([O:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: OCc1ccncc1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Yield: 87 %

Procedure:
The general procedure used for the preparation of Example 3 was used in step 1 of the preparation of Example 4 from 1-chloro-4-(4-chlorophenylamino)phthalazine and 4-pyridyl-carbinol; (87% yield). TLC (20% acetone/dichloromethane): Rf=0.26.
Reaction SMILES: NC1C(C=O)=CC=CC=1C(OC)=O.[NH2:14][C:15]1[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>>[NH2:14][C:15]1[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]
Reactant: Nc1c(Br)cccc1C=O
Agent: COC(=O)c1cccc(C=O)c1N
Product: Nc1c(Br)cccc1CO

Procedure:
In a similar manner to the preparation of methyl 2-amino-3-formylbenzoate, 2-amino-3-bromobenzaldehyde (3.28 g, quantitatively) was obtained from (2-amino-3-bromophenyl)methanol (3.27 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](I)[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:6].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH3:26])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:6]
Reactant: CC(C)COC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(I)n2)s1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C)COC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
The 4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]-2-iodo-pyrimidine (0.082 g, 0.17 mmol) is heated to reflux with aniline (0.032 g, 0.34 mmol) and dry p-toluene sulfonic acid (0.026 g, 0.136 mmol) in dry dioxane for five hours.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH3:20])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]([O:17]CC)=[O:16].O.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH3:20])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1ncn2c3cccc(Cl)c3c(=O)n(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c2c(Cl)cccc2n2cnc(C(=O)O)c12
Temperature: 0 °C
Yield: 102.2 %

Procedure:
Ethyl 6-chloro-4,5-dihydro-4-methyl-5-oxo-imidazo(1,5-a)-quinazoline-3-carboxylate (2.27 g,7.4 mmol) in a mixture of 50 ml of ethanol, 25 ml of water and 4.6 ml of 4M aqueous sodium hydroxide was refluxed for 1 h. Then the mixture was cooled to 0° C. and neutralized by addition of 4.6 ml of 4M hydrochloric acid. The precipitate was filtered off, rinsed with water and dried to give 2.1 g (100%) of 6-chloro-4,5-dihydro-4-methyl-5-oxo-imidazo(1.5-a)quinazoline-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23]I)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:23][CH:9]([C:10]#[N:11])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:25]([O:27][CH3:28])=[O:26])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCc1cccc(F)c1F
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C#N)c1cccc(F)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound (12.0 g). MS 377.3 (M+Na).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:13]([OH:27])=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8].I[CH2:29][CH3:30].CCOC(C)=O.CCCCCC>CN(C=O)C.O.CCOC(C)=O>[CH2:7]([O:9][C:10]([C:12]1[C:13]([O:27][CH2:29][CH3:30])=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:11])[CH3:8]
Reactant: CCI
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
354 mg (2.6 mmol) K2CO3 was added to a solution of 700 mg (2.3 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in DMF (9 ml) and stirred for 60 min at RT. 190 μl (2.3 mmol) iodoethane was then added and the RS was stirred for a further 16 h at RT. The solution was subsequently diluted with water and EtOAc. The organic phase was separated, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:3) of the residue, 168 mg (0.5 mmol, 22%) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[O:12][CH3:13].[CH2:15](I)[CH3:16]>CN(C)C=O>[CH2:15]([N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[C:11](=[O:14])[O:12][CH3:13])[CH3:16]
Reactant: COC(=O)Nc1ccccc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)c1ccccc1C
Reaction time: 4 h

Procedure:
5.1 g (0.2 mol) of sodium hydride are added a little at a time to 30 g (0.18 mol) of methyl N-(o-methylphenyl)-carbamate (Example 1a) in 200 ml of dimethylformamide. After the evolution of gas has ceased, 30 g (0.2 mol) of ethyl iodide are added dropwise, the reaction mixture being lightly cooled in a water bath. A white solid is precipitated. After about 4 hours, the reaction mixture is diluted with water and the aqueous phase is extracted three times with ether. The organic phase is dried over MgSO4 and evaporated down. The residue is distilled. 32.5 g (0.17 mol=93%) of the title compound are obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:18]([O:25][CH2:26][C:27](N(OC)C)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][CH2:26][C:27]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)COCc1ccccc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)COCc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-benzyloxy-N-methoxy-N-methylacetamide. The product is used in crude form in the following reaction.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[S:7][N:6]=1)([CH3:4])[CH3:3].[CH3:11][CH:12]([CH2:16][CH2:17][Cl:18])[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:18][CH2:17][CH2:16][CH:12]([CH3:11])[C:13]([NH:10][C:8]1[S:7][N:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1)=[O:14]
Reactant: CC(C)(C)c1cc(N)sn1
Reactant: CC(CCCl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)ns1
Yield: 12 %

Procedure:
To a solution of 2.4 g of 3-(1,1-dimethylethyl)-5-aminoisothiazole dissolved in 150 ml of toluene under nitrogen was added 2.3 g of 2-methyl-4-chlorobutyric acid chloride. The reaction mixture was refluxed for about 24 hours and cooled. The solvent was evaporated under reduced pressure, and the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford, following crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide. Yield 12%. mp 144°-146° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=O.[CH3:32][NH2:33].O>CCO>[CH3:32][NH:33][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:8]2)=[O:2]
Reactant: CN
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.085 mmol) and methylamine (1 mL, 2M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., 3 mL of water was added. The resulting suspension was filtered, and the crude solid was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2+1% AcOH) to give 13 mg of the title compound as a white solid. MS: (+) m/z 411.01 (M+1).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH2:6][CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:8])C.[H-].[Li+].[Al+3].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>O1CCOCC1.C(OCC)(=O)C>[CH3:4][NH:5][CH2:6][CH:7]([C:9]1[C:10]2[CH2:11][CH2:12][N:13]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[CH:15]=[CH:16][CH:17]=1)[OH:8]
Reactant: CCOC(=O)NCC(O)c1cccc2c1CCN2C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNCC(O)c1cccc2c1CCN2Cc1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
A solution of 113 g of the compound of Step C in 1,130 ml of dioxane was added slowly with stirring under an inert atmosphere to a suspension of 110 g of aluminium-lithium hydride and 55 g of aluminium chloride in 1,700 ml of dioxane. After 1 hour of stirring between 80° C. and 50° C. and cooling to 10° C., the excess hydride was destroyed with an ammonium chloride-dioxane-water mixture. The resulting mixture was diluted with water, filtered, and the filtrate was concentrated by eliminating about 1,000 ml of solvent. After adding water and extracting with methylene chloride, the extracts were washed with water saturated with sodium chloride, dried and evaporated to dryness to obtain 95 g of crude product. The crude product was refluxed with stirring in 1 liter of ethyl acetate and 8.5 g of insoluble matter corresponding to the hydrochloride of the expected product were filtered off and melted at ≃179° C. The filtrate was concentrated hot to 400 ml, left to crystallize to obtain 55.19 g of 2,3-dihydro-α-[(methylamino)-methyl]-1-benzyl-1H-indol-4-methanol melting at ≃112° C.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.[Cl:11]C1C2SC=CC=2N=CN=1>>[Cl:11][C:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Clc1ncnc2ccsc12
Reactant: O=c1[nH]cnc2sccc12
Product: Clc1ncnc2sccc12
Yield: 93 %

Procedure:
Starting from thieno[2,3-d]pyrimidin-4(3H)-one (204) [J. Med. Chem., 1999, 42, 26, 5437-5447, Bull. Soc. Chim. Fr., 1975, 587-591] and following the procedure described above for the synthesis of compound 20 (scheme 4, example 22), title compound 205 was obtained in 93% yield. LRMS (M+1) 169.1 (100%), 171.1 (32%).