Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:23]([F:24])=[C:22]([F:25])[C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[CH3:21])C[O:11][C:12](=[O:13])[C:7]=2[CH:6]=1)=[O:4].OCC(CO)O.Cl>C1COCC1>[F:24][C:23]1[C:22]([F:25])=[C:8]([NH:9][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])[C:7]([C:12]([OH:13])=[O:11])=[CH:6][C:5]=1[C:3]([NH:2][CH3:1])=[O:4]
Reactant: CNC(=O)c1cc2c(c(F)c1F)N(c1ccc(I)cc1C)COC2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CNC(=O)c1cc(C(=O)O)c(Nc2ccc(I)cc2C)c(F)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide in THF (10 mL) is added polymer bound glycerol, (0.33 g, 200–400 mesh) and 10 mL of 1.0 M HCl solution. After stirring for 48 hours at room temperature, the resin is filtered off and the filtrate is transferred to a separatory funnel and partitioned with ethyl acetate. The organics are washed twice with 1.0 M HCl, twice with saturated brine solution, collected, dried over Na2SO4, filtered and concentrated in vacuo affording 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid (0.11 g, 76.2%); mp 254–259° C.; 1H NMR (400 MHz; DMSO-d6) 9.31 (s, 1H), 8.19 (s, 1H), 8.07 (d, 1H, J=7.2), 7.56 (s, 1H), 6.69 (t, 1H, J=5.6), 2.74 (d, 3H, J=4.4), 2.20 (s, 3H); MS (APCI)m+1=447; Anal.calcd/found for C16H13F2IN2O3, C 43.07/43.26, H 2.94/3.07. N 6.28/6.10.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH:12]1([CH2:11][C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F

Procedure:
4-Cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid ethyl ester (A1-III) was taken in ethanol. To it a solution of potassium hydroxide in water was added and the reaction was refluxed for 18 hrs. Ethanol was evaporated; residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified using dilute HCl and extracted with ethyl acetate. Ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. Solvent was evaporated to get 4-cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid (A1-IV).
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)O1>COCCOC.O>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:22]=[N:23]2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Yield: 91.3 %

Procedure:
A mixture of 2-chloro-4-iodofuro[2,3-c]pyridin-7-amine (7.7 g, 26.2 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (10.52 g, 27.7 mmol) in 1,2-dimethoxyethane (300 mL) and water (100 mL) was sparged with N2 for 15 min, then treated with K2CO3 and Pd(PPh3)4. After sparging again with N2 for 5 min, the mixture was heated at reflux 4-6 h. The 1,2-dimethoxyethane was removed in vacuo, water was added and the mixture extracted with DCM. The combined DCM extracts were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography using triethylamine-coated silica (2% MeOH:DCM) to afford 10 g (80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.44-1.55 (m, 9H) 1.90-2.12 (m, 2H) 2.21 (d, J=10.61 Hz, 2H) 2.84-3.03 (m, 2H) 4.22-4.44 (m, 3H) 5.26 (br s, 2H) 6.77 (s, 1H) 7.65 (s, 1H) 7.73-7.79 (m, 1H) 7.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Temperature: 25 °C

Procedure:
A mixture of 7.85 g (0.03 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 6.15 g (0.033 m) of N-(2-chloroethyl) morpholine HCl and 7.08 g (0.07 m) of triethylamine in 250 cc of ethanol was refluxed for 6 hr. and filtered hot. Treatment of the hot reaction solution with excess HCl 6 hr. and cooling to room temperature afforded crude product. Crystallization from 75% EtOH afforded analytical material mp. 238°-40°C.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:33][CH2:32][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:32][CH2:33]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: CN
Product: CNc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-Chloro-pyridine-3-sulfonyl)-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 206) and methyl amine. Off-white solid. MS (ESI): 499.3 (MH+).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25](=O)[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[CH2:22][C:21]=2[CH:31]=1.[OH-].[NH4+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(O)(C)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[CH2:22][C:21]=2[CH:31]=1
Reactant: O=C1Nc2ccc(Cl)cc2Cn2cccc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cccc32)CC1
Temperature: 60 °C

Procedure:
A mixture of 15 ml. of dry toluene, 1.5 ml. of anisole and 0.8 ml. of titanium tetrachloride is cooled under argon. A solution of 2.8 ml. of N-methylpiperazine in 10 ml. of toluene is added. A 1.55 g. portion of 7-chloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one and 1.4 ml. of N-methylpiperazine are added in succession. The reaction mixture is heated at reflux for 5 hours, cooled to 60° C. and 2.2 ml. of isopropanol, 2 ml. of concentrated ammonium hydroxide and 1 g. of celite are added. After cooling to 30° C., 20 ml. of toluene are added and the mixture is filtered and washed with toluene. The toluene layer is washed twice with water, concentrated to remove the solvent and cooled. The solid is washed onto a filter with hexane, treated with 10 ml. of 1 N acetic acid and the insoluble material is collected and washed with water. The aqueous layer is treated with 10 ml. of 1 N ammonium hydroxide. The precipitate is collected, washed with water, dried in vacuo and recrystallized from ethanol, giving the desired product, m.p. 186°-188° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([O:17][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
In a round-bottomed flask, 1-chloro-3-(3,4-dichlorophenyl)propan-2-one (0.545 g, 2.30 mmol) was taken up in 2 mL acetone, and acetic acid (0.26 mL, 0.28 g, 4.6 mmol) was added. The solution was cooled in an ice water bath, and triethylamine (0.64 mL, 0.47 g, 4.6 mmol) added dropwise via syringe over 30 minutes. The reaction mixture was then stirred overnight. Precipitated triethylammonium chloride was removed by filtration, and the filtrate was evaporated, taken up in 10 mL ethyl acetate, washed twice with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (10-30% ethyl acetate in hexanes) to give a pure product (0.200 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.71 (s, 2H) 4.71 (s, 2H) 7.05 (dd, J=8.2, 2.2 Hz, 1H) 7.32 (d, J=2.0 Hz, 1H) 7.41 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>C(O)COCCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCCO
Solvent: OCCOCCO
Product: COc1ccccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 21.7 %

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.2 mmol) was dissolved in diethylene glycol(10 ml) and 4-amino-1-butanol(175 μl, 1.9 mmol) was added. It was reacted at the same condition of Step 3 in the Example 38 to obtain 120 mg of desired compound as solid in 39% of yield.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:11][C:12]1[C:13]([OH:18])=[CH:14][C:15]2[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:10])([CH3:3])[C:16]=2[CH:17]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21

Procedure:
36.6 g (0.2 mol) of 2,5-dichloro-2,5-dimethylhexane, 34.6 g (0.2 mol) of 2-bromophenol and 400 ml of dichloromethane were introduced successively into a three-necked flask. 26.6 g (0.2 mol) of AlCl3 were added in small amounts at 0° C. and stirring was carried out until gas evolution had ceased (violent reaction). The reaction mixture was poured into water and the organic phase was separated by settling, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). After evaporating the solvents, 20.6 g (36%) of the expected phenol were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:12]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1Br
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Step P (1): To a solution of 4-bromo-3-methoxyaniline (0.500 g, 2.48 mmol) in dichloromethane (10 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.575 g, 2.48 mmol). The resulting mixture was stirred at rt for 3 h. The crude reaction mixture was loaded onto silica gel and purified using silica gel chromatography (3-60% EtOAc/hexanes, linear gradient) to afford 1-bromo-4-isothiocyanato-2-methoxybenzene (0.48 g, 75% yield) as an off white solid. LC-MS (M+H)+ 244.0. 1H NMR (400 MHz, methanol-d4) δ ppm 7.53 (d, J=8.56 Hz, 1 H) 6.94 (d, J=2.27 Hz, 1 H) 6.79 (dd, J=8.56, 2.27 Hz, 1 H) 3.86 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31](Br)[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:33])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCC(=O)c5ccccc5)cc4)cc3)n(C)c(=O)c12
Yield: 59 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (413 mg), phenacyl bromide (315 mg) and potassium carbonate (436 mg) in DMF (7 ml) was stirred at room temperature for 15 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform, washed with water, dried, and concentrated. The residue was recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (313 mg).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH3:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:50]>C(O)C>[Na+:50].[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH3:34])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (170 mg) is dissolved in ethanol (2 ml), and thereto is added 2N-aqueous sodium hydroxide solution (352 μl) and the mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To the residue are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (147 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (106 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (151 mg). MS (m/z): 695 [M−Na]−
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>COCCO>[F:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11]([OH:12])=[N:6][CH:5]=[N:7]2)=[CH:14][CH:15]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: Oc1ncnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Formamidine acetate (20.13 g, 193.4 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (15 g, 96.7 mmol) in 2-methoxyethanol (97 ml) and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 M, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4-ol as an off-white solid (10.35 g, 65% yield):
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:4]2[C:5]([N:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8](=[O:9])[C:3]=12)=[O:6]>CO.[BH4-].[K+]>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:4]2[C:3]=1[CH:8]([OH:9])[N:7]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]2=[O:6]
Reactant: CC(C)CN1C(=O)c2cccc(F)c2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)CN1C(=O)c2cccc(F)c2C1O
Temperature: 20 °C
Reaction time: 19 h
Yield: 88.9 %

Procedure:
4-Fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1 starting with 3.9 g of 3-fluoro-N-isobutylphthalimide in 20 cm3 of methanol and 0.95 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 19 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off, washed with cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 3.5 g of 4-fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a sticky white powder. (Rf=0.36, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (60/40 by volume)).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-:12].[Na+].Cl>CO>[CH3:8][C:5]1[N:4]=[C:3]([C:9]([OH:11])=[O:10])[C:2]([C:5]2[O:12][CH:2]=[CH:3][N:4]=2)=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: Cc1ccc(Br)c(C(=O)O)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ncco2)c(C(=O)O)n1
Reaction time: 1 h

Procedure:
To the title compound of step C (56 mg, 0.3 mmol) was added MeOH (0.6 mL) and 2M NaOH(aq) (0.6 mL). After 1 h at rt, 1M HCl(aq) was added. The reaction mixture was concentrated to give the title compound (52 mg) that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C10H8N2O3, 204.2; m/z found 205.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[N:7]2.[CH3:26][Mg]Br.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[CH3:26])=[CH:14][CH:13]=1)=[N:7]2
Reactant: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)benzaldehyde (9-1, 0.500 g, 1.450 mmol) in anhydrous methylene chloride (10 mL) was added methymagnesium bromide (2.072 mL, 2.9 mmol, 1.4M in toluene/tetrahydrofuran (75:25)) at 0° C. After 15 minutes, the reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, water, then brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure gave the title compound. MS (M+H+): calculated=361.85, observed=361.1.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:20])[C@H:10]([NH:14]C(OCC)=O)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[NH2:14][C@H:10]([CH2:11][O:12][CH3:13])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: CCOC(=O)N[C@H](COC)C(=O)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC[C@@H](N)C(=O)NCc1ccccc1

Procedure:
To a 100 mL single-neck flask, 5.6 g (0.02 mol) (R)-N-benzyl-2-(ethoxycarbonylamino)-3-methoxypropionamide and 50 mL 31% concentrated hydrochloric acid were added, the mixture was heated and refluxed for 6-10 hr. After the reaction was completed, 30% sodium hydroxide solution was added to adjust the pH value of the system to 8-9. The reaction liquid was extracted with 50 mL×2 dichloromethane, and dried over anhydrous sodium sulfate. The product can be directly used in following synthesis without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@:22]([C:30]3[S:31][CH:32]=[C:33](B4OC(C)(C)C(C)(C)O4)[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@:22]([C:30]3[S:31][CH:32]=[C:33]([N:1]=[N+:2]=[N-:3])[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(B4OC(C)(C)C(C)(C)O4)cs3)COCC[C@H]2CS1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(N=[N+]=[N-])cs3)COCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Sodium azide (177 mg) and copper (II) acetate (99.2 mg) were added to a solution of (±)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,8aR*)-8a-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (790 mg) in methanol (88 ml). The mixture was stirred at room temperature overnight, and then the excess of methanol was evaporated under reduced pressure. An ammonium chloride solution was added to the residue, and the aqueous layer was with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (503 mg).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.[CH3:16][NH:17][CH2:18][CH2:19][OH:20].C(NCCO)C>>[CH:9]([C:8]1[CH:7]=[C:6]([CH:15]=[CH:14][CH:13]=1)[C:2]([N:17]([CH2:18][CH2:19][OH:20])[CH3:16])=[O:3])=[O:11]
Reactant: CNCCO
Reactant: COC(=O)c1cccc(C2OCCO2)c1
Agent: CCNCCO
Product: CN(CCO)C(=O)c1cccc(C=O)c1

Procedure:
The title compound was prepared as described in Example 2 Step 2 with methyl 3-(1,3-dioxolan-2-yl)benzoate and N-methylethanolamine replacing methyl 4-(1,3-dioxolan-2-yl)benzoate and N-ethylethanolamine respectively.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>CCO>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:18][NH:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])#[N:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1cccc(C#N)c1
Yield: 77 %

Procedure:
3-Cyanobenzaldehyde (40.0 mmol) suspended in EtOH (100 mL) was added to a stirred solution of tert-butylcarbazate (40.0 mmol) in EtOH. The mixture was heated at reflux temperature and after 4 h the EtOH was partially evaporated in vacuo. Water (100 mL) was added and the precipitated product was collected by filtration and washed with diethylether to give tert-butyl 2-(3-cyanobenzylidene)-1-hydrazinecarboxylate as a white solid.