Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:13])[CH:7]=[C:8]([CH2:11][OH:12])O[CH:10]=1.O.[NH3:15]>>[O:13]1[C:6]2[CH:7]=[C:8]([CH2:11][OH:12])[N:15]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=c1cc(CO)occ1OCCCl
Solvent: O
Product: OCc1cc2c(cn1)OCCO2
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To 229 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one (crude product), 572 mL of 28% ammonia water was added, the mixture was stirred for 7 hours at 85° C. and allowed to stand overnight at room temperature. The reaction mixture was extracted 4 times with 500 mL of 2-propyl acetate. The organic layer was combined therewith and the solvent was evaporated under reduced pressure to give 90.5 g of (2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol as a brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:27])[CH:3]=1.C(N1C2C(OC3C=CC(N[C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[S:48])=CC=3F)=NC=NC=2C=C1)C>>[C:22]([N:19]1[CH2:20][CH:21]=[C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:25]=[CH:26][C:2]([NH:1][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[S:48])=[CH:3][C:4]=3[F:27])[CH:13]=2)[CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: CCn1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)CC1
Yield: 70 %

Procedure:
Starting from compound 391 and following the procedure described for compound 31b (Scheme 5, step 4, example 28); title compound 385 was obtained in 70% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.45 (s, 1H), 11.83 (s, 1H), 8.49 (dd, J=5.5 Hz, J=0.8 Hz, 1H), 8.00 (d, J=11.9 Hz, 1H), 7.58-7.49 (m, 3H), 7.41-7.35 (m, 2H), 7.21-7.13 (m, 2H), 6.65 (dd, J=5.5, 1 Hz, 1H), 6.50 (m, 1H), 4.2 (m, 1H), 4.15 (m, 1H), 3.83 (s, 2H), 3.70-3.67 (m, 2H), 2.68 (m, 1H), 2.59 (m, 1H), 2.09 (s, 1.5H), 2.04 (s, 1.5H). LCMS: 579.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (95 mg, 75%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:37])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:21][C:22]([C:24]3[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=3)=[O:23])=[CH:15][CH:14]=2)[CH:12]=1.CCN(C(C)C)C(C)C.CC(C)=O.[Na+].[I-]>>[CH3:5][O:4][CH2:3][CH2:2][O:35][C:33](=[O:34])[C@H:32]([OH:36])[CH2:31][N:20]([CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=2[F:37])=[CH:18][CH:17]=1)[NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=1)=[O:23]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: COCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
1-Bromo-2-methoxyethane (12.2 μL, 129 μmol) was added to a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 μmol) and DIPEA (45.1 μL, 259 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was heated at 60° C. for 4 hours. NaI (19.4 mg, 129 μmol) was added and the reaction was monitored for 2 hours. Additional 1-bromo-2-methoxyethane (3 eq.), DIEA (4 eq.), and NaI (3 eq.) were added and the heating continued overnight. Additional 1-bromo-2-methoxyethane (3 eq.), NaI (3 eq.), and DIEA (3 eq.) were added and heating continued overnight. The mixture was then concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (2.6 mg, purity 99%). MS m/z [M+H]+ calc'd for C24H25ClFN3O7, 522.14. found 522.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-:16])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncc(F)c(C)c1Br
Solvent: ClCCl
Product: Cc1c(F)c[n+]([O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-2,4-dimethyl-pyridine (220 mg, 1.08 mmol) and 3-chloroperoxybenzoic acid (399 mg, 1.62 mmol) in dichloromethane (3 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous sodium thiosulfite (10 mL) followed by saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-10% methanol in DCM). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (220 mg, 93%), which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+].Cl>O>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
Water (approximately 15 ml) was added to a solution of ester 28b (486 mg, 1.00 mmol) in 50 ml of an 80/20 (v/v) (methanol/THF) solution, until it remained milky white with vigorous stirring. To this suspension was added lithium hydroxide monohydrate (213 mg, 5.1 mmol), the reaction mixture was refluxed overnight and then was acidified with concentrated HCl. Water (approximately 20 ml) was added and the solution was cooled, filtered, washed several times with water, and air dried, yielding 422 mg (89%) of a white waxy powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[N:4][CH:3]=1.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[C:7]([C:8]#[N:10])=[CH:6][C:5]([C:11]([F:13])([F:12])[F:14])=[N:4][CH:3]=1
Reactant: NC(=O)c1cc(C(F)(F)F)ncc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)ncc1Br
Temperature: 70 °C
Yield: 94 %

Procedure:
To a 100 mL round bottom equipped with a stir bar, condenser and nitrogen inlet was charged 5.2 g (19.3 mmol) of 5-bromo-2-trifluoromethyl-isonicotinamide. The solid was diluted with 12 mL of phosphorus oxychloride. The mixture was heated at 70° C. for 3 hr. The mixture was cooled to ambient temperature and poured onto ice. The mixture was neutralized with the careful addition of 50% sodium hydroxide. The resulting off-white solid was collected by filtration, washed with water and dried in vacuo at 50° C. for 18 h. This afforded 4.5 g of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 as an off-white solid in a 94% yield. 1HNMR (CDCl3), δ, 9.03 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: N#N.C(OC(=O)[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[S:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1)(C)(C)C.[ClH:25]>C(Cl)Cl.O1CCOCC1>[ClH:25].[NH2:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[S:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cc2nc(NC(=O)OC(C)(C)C)cs2)s1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2nc(N)cs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-acetyl-thiophen-2-ylmethyl)-thiazol-4-yl]-carbamic acid tert-butyl ester (75 mg, 0.22 mmol) in dry CH2Cl2 (2.2 mL) was treated at 0° C. with HCl (0.55 mL of a 4M solution in dioxane, 2.22 mmol). After stirring at 0° C. for 1 h, the reaction mixture was stirred at rt for 16 h. The solvents were removed under reduced pressure to give the title compound as a light brown solid. LC-MS-conditions 02: tR=0.71 min, [M+AcCN+H]+=280.14.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32]C(N)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[C:15]([C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:32]=[CH:33][C:28]([N:24]4[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:29][CH:30]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)(=[O:19])[CH:16]([CH3:17])[CH3:18]
Reactant: COC(=O)c1sc(C(=O)C(C)C)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CC(C)C(=O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-isobutyrylthiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 410.54 (C22H26N4O2S) was obtained in this way; MS (ESI): 411 (M+H+).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:21]3)C(=O)C(F)(F)F)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(N(Cc1cc2c(cn1)OCCO2)CC1CCCN(CCn2c(=O)ccc3ncc(F)cc32)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
To a solution of 0.15 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamide in 2 mL of dichloromethane, 85 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 24 μL of acetic acid were added, subsequently, 0.13 g of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, chloroform was added, and a saturated aqueous sodium hydrogen carbonate solution was added thereto under cooling with ice and adjusted to pH 8.0. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.21 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamide as a yellow solid. To 0.21 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-3-ylmethyl)acetamide, 3 mL of methanol and 0.7 mL of water were added, and thereto was added 62 mg of potassium carbonate. The mixture was stirred at room temperature for 1 hour 15 minutes, then stirred at 40 to 50° C. for 1 hour, and stirred at 50 to 60° C. for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, chloroform and water were added to the resultant residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with hexane:ethyl acetate=92:8 to 88:12 to obtain 0.18 g of 1-(2-(3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[OH:13].[O-]CC.[Na+]>C(O)C>[C:3]([CH2:2][S:1][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[OH:13])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: OC(CCCCl)c1ccco1
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCCC(O)c1ccco1

Procedure:
To a stirred, refluxing mixture of ethyl mercaptoacetate, and 4-chloro-1-(2-furyl)-1-butanol (Example 160), and sodium ethoxide in ethanol. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again conentrated to give an oil.
Reaction SMILES: [OH:1]O.[CH2:3]([NH:5]/[C:6](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1)[CH3:4]>CO.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:3]([NH:5]/[C:6](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1=[O:1])[CH3:4]
Reactant: CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: OO
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCN/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
3.2 ml (0.031 mol) of aqueous 30% hydrogen peroxide, dissolved in 15 ml of methanol, was added dropwise, while vigorously stirring, to a solution of 1.97 gm (0.007 mol) of (E)-2-[(ethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and 10 ml of an aqueous 16% solution of titanium (III) chloride in 100 ml of methanol and 20 ml of water. The course of the reaction was monitored by thin-layer chromatography. After the reaction had ended, the mixture was diluted with 300 ml of water, and the precipitate thus obtained was suction-filtered off and then recrystallized twice from ethanol. 1.75 gm (84% of theory) of pale yellow crystals, m.p. 183°-185° C., were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14]([OH:16])([CH3:18])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: O=C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3-bromo-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione (0.04 g, 1.37 mmol, 1 equiv) in dry THF was added CH3MgBr (0.27 mL, 2.74 mmol, 2 equiv) dropwise at 0° C. The resulting mixture was stirred for 4 h at 0° C. The reaction was quenched with saturated NH4Cl, extracted with EtOAc, and dried over Na2SO4. The organic extract was concentrated under reduced pressure to give the desired product. MS (ESI): 309, 311 (MH+).
Reaction SMILES: C([S:4][C:5]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C.[OH-].[Na+].Cl>>[SH:4][C:5]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)Sc1c(C(=O)N(CC(=O)O)C2CCCC2)cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(C(=O)c1cccc(C(F)(F)F)c1S)C1CCCC1

Procedure:
N-(2-Acetylthio-3-trifluoromethylbenzoyl)-N-cyclopentylglycine (1.4 g, 3.6 mmol) and 1 N sodium hydroxide solution were stirred 4 hours at room temperature, then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were washed with water and brine, then dried and concentrated to a yellow gum which solidified on standing. Recrystallization from hexane/ethyl acetate gave a white solid, m.p. 144°-146° C.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:13]([N:15]1[CH2:29][CH2:28][CH2:27][C@H:16]1[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[NH:1]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:2]([C:13]([N:15]1[CH2:29][CH2:28][CH2:27][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Substance [5] (52.78 g, 106.29 mM) was dissolved in methanol (300 ml). 1 N NaOH (150 ml, 1.4 molar excess) was added dropwise during 20 minutes with ice cooling and then the mixture was stirred at room temperature. 1 N HCl (43.71 ml, 0.4 molar excess) was added with ice cooling to adjust to pH 7 and methanol was distilled off in vacuo. The aqueous layer was washed with ether (150 ml) and the pH of the aqueous layer was adjusted to pH 3 by adding 1 N HCl (110 ml). The solution was extracted twice with ethyl acetate (300 ml and 150 ml). The extract was dried by adding anhydrous sodium sulfate, then concentrated in vacuo. Ether and hexane were added to the residue to obtain the precipitate. The same operation was repeated and the precipitate was dissolved in ethyl acetate, then dried in vacuo to obtain the foaming solid substance [6] (32.27 g, yield: 77.75%).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:33]([N:35](CC)[CH2:36]C)C.CNC.O1CCCC1>C(Cl)Cl>[C:6]1([CH2:12][O:13][C:14]([C:16]2([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:35]([CH3:36])[CH3:33])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1ccc(CO)cc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
Under ice-cooling, 1 g (9 mmol) of methanesulfonyl chloride was added dropwise to a solution of 3 g (8 mmol) of 1-[[[4-(hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester and 2.46 g (24 mmol) of triethylamine in methylene chloride. After the mixture was stirred at room temperature for 1 hour, 20 ml of 2N dimethylamine-tetrahydrofuran solution was added, and the mixture was stirred overnight. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 700 mg (22%) of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20](OC)=[C:21](O)[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N1CCC[C@H](O)C1)=O)(C)(C)C>ClCCl>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[N:15][CH:16]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc2ncncc2c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 29.3 %

Procedure:
Diethyl azodicarboxylate (5.7 ml) was added to 4-chloro-6-hydroxy-7-methoxyquinazoline (4.39 g; prepared as described in Example 1 (Preparation of starting materials)), triphenylphosphine (8.2 g) and (3S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (Commercially Available—CAS Registry No 14390044-1) (6.29 g) in dichloromethane (130 ml) and the reaction mixture was stirred at 40° C. for 6 hours. This was allowed to stand overnight at −18° C. then filtered. The filtrates were purified by flash column chromatography eluting with acetone/isohexane/triethylamine (17/82/1) to give 4-chloro-7-methoxy-6-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yloxy)]quinazoline as a white solid (0.794 g, 48%); Mass Spectrum: (M+H)+394.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([OH:31])=[O:30])=[C:24]2[C:28]=1[O:27][CH2:26][CH2:25]2.Cl>C(O)C.O>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:29]([OH:31])=[O:30])=[C:24]4[C:28]=3[O:27][CH2:26][CH2:25]4)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: Nc1ccc(C(=O)O)c2c1OCC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Yield: 65.1 %

Procedure:
(7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (82 mg, 3.07 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 22e (500 mg, 2.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V/V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 15 hours and cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (0.75 g, yield: 65.0%) as a white solid.