Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=O)[CH2:12]Cl)=[C:9]([CH3:15])[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:17]([NH2:19])[S:18][CH:12]=3)=[C:9]([CH3:15])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1[nH]c2ncc(Br)cc2c1C(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1[nH]c2ncc(Br)cc2c1-c1csc(N)n1
Yield: 99.2 %

Procedure:
A solution 1-(5-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-chloro-ethanone (0.56 g, 1.97 mmol) and thio urea (0.16 g, 2.17 mmol) in ethanol (19 mL) was stirred at 80° C. for 2 hours. The resulting precipitate was filtered, washed with MeOH, and dried under vacuum to give 4-(5-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.604 g, 99% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:20]=[C:19]([OH:21])[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([OH:21])[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)NC(c1ccc(OC(C)C)cc1)N=C2O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cc3)nc2c1
Reaction time: 1 h
Yield: 73 %

Procedure:
2-(4-isopropoxyphenyl)-7-methoxy-1,2-dihydroquinazolin-4-ol (685 mg, 2.193 mmol) was dissolved in DCM (10 mL) followed by the addition of DDQ (597 mg, 2.63 mmol). The reaction was stirred for 1 h. The reaction was diluted with DCM and filtered through celite. The filtrate was collected and concentrated under vacuum. The crude material was purified by silica gel chromatography using 40% EtOAc in hexanes. The product fractions were collected and the solvent removed under vacuum to give 2-(4-isopropoxyphenyl)-7-methoxyquinazolin-4-ol (495, 73% yield). MS: MS m/z 311.1 (M++1).
Reaction SMILES: O=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[C:7]1([NH:13][NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH3:6][C:2]1[CH:3]=[C:4]([NH2:5])[N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=1
Reactant: CC(=O)CC#N
Reactant: NNc1ccccc1
Solvent: CCO
Product: Cc1cc(N)n(-c2ccccc2)n1

Procedure:
Into a 1000-mL 3-necked round bottom flask, was placed a solution of 3-oxobutanenitrile (23 g, 277.11 mmol, 1.00 equiv) in ethanol (400 mL), 1-phenylhydrazine (30 g, 277.78 mmol, 1.00 equiv). The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to yield 3-methyl-1-phenyl-1H-pyrazol-5-amine as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][CH2:11][CH2:10][CH:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:14]([CH:9]2[C:8]3[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=3)[O:12][CH2:11][CH2:10]2)=[O:16])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)C1CCOc2c1cccc2[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and 4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were added N-hydroxybenzotriazole hydrate (2.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and the mixture was stirred at room temperature. After the completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g).
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.COCOC.C[C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>S1(CCCC1)(=O)=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][O:22][CH3:20])[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: COCOC
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
16.7 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2), 2.18 g of trimethyl borate and 2.45 g of methylal (prepared as described in Preparation 5) were added to 20 ml of sulfolane. The mixture was cooled to 10° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 10° C. for 1.5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2. 1.94 g (yield 79%) of the title compound were produced with high purity.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1.B.O1CCCC1>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][C:11]=2[CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2cc(Cl)ccc2o1
Reaction time: 24 h
Yield: 46.6 %

Procedure:
To a tetrahydrofuran solution (12 mL) of 5-chlorobenzofuran-2-carboxylic acid (620 mg, 3.15 mmol), borane-tetrahydrofuran complex (7.88 mL, 7.88 mmol, tetrahydrofuran solution) was added at 0° C. and the resultant solution was stirred at room temperature for 3 hours, at 60° C. for 1 day, and at room temperature for 1 day. After completion of the reaction, concentration under reduced pressure was carried out three times with adding methanol to the reaction solution and the concentrated solution was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1 (v/v)) to obtain the title compound (268 mg, yield 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].CC(=CC)C.Cl([O-])=[O:24].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]([C:5]([CH3:7])([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([OH:24])=[O:16])[CH3:6])=[O:17])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
3.33 g (14.1 mmol) of 2-(3-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 55A])] was dissolved in 60 ml of tert.-butanol; 7.5 ml (70.5 mmol) of 2-methyl-2-butene was added, followed by a solution of 4.14 g (36.6 mmol) of sodium chlorite and 3.30 g (21.1 mmol) of sodium dihydrogen phosphate in 35 ml of water. After 2 hours, the reaction mixture was poured into crashed ice/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by recrystallisation from EtOAc/heptane to give 3.19 g of the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]([F:18])([CH3:17])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:34][CH3:35])[C@@H:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)[OH:22]>>[F:18][C:2]([F:1])([CH3:17])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5](=[O:7])[NH:19][C@H:20]([C:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)=[O:22])[CH2:34][CH3:35]
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Product: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCOCC1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
By proceeding in a similar manner to Example 1 above but using (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-pentanoic acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol there is prepared Morpholine-4-carboxylic acid {(S)-3,3-difluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-but}-amide as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@@H]1O
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a suspension of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (679 mg) in 14 ml of tetrahydrofuran was added lithium tri-tert-butoxyaluminohydride (676 mg) at 5° C. The reaction mixture was allowed to stir at 5°-10° C. for 45 minutes, then the solvent was removed in vacuo. To the residue was added 20 ml ice-water. Then, the mixture was acidified with 1N hydrochloric acid and extracted with dichloromethane (25 ml×2). The combined extracts were washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) eluted with a mixture of dichloromethane and ethyl acetate (10:3) to give pale yellow crystals of cis-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (677.4 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])[CH:13]=[C:12]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(CCCN)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCc1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
The title compound is prepared by the reaction of the compound of Example 58 with methacryloyl chloride in the presence of triethylamine in toluene.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Br:15]Br>>[Br:15][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC[C@H](C)COc1ccccc1C#N
Reactant: BrBr
Product: CC[C@H](C)COc1ccc(Br)cc1C#N
Reaction time: 24 h

Procedure:
A mixture of compound 39 (4.25 g, 0.-22 mol), bromine (12.31 g, 0.077 mol was then added and heating continued for another 24 h. The resultant solution was washed with a saturated solution of sodium thiosulphate and finally with water. The dichloromethane solution was dried (MgSO4) and evaporated in vacuo and the crude oil was purified by column chromatography (10% petrol/dichloromethane) to yield a fawn oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10](O)[C@H:11]([O:27][CH:28]([CH3:30])[CH3:29])[C:12]([N:14]2[C@@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:16][C:15]2=[O:26])=[O:13])=[CH:6][CH:5]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@H:11]([O:27][CH:28]([CH3:29])[CH3:30])[C:12]([N:14]2[C@@H:18]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][O:16][C:15]2=[O:26])=[O:13])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc([C@@H](O)[C@H](OC(C)C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C[C@H](OC(C)C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 101 %

Procedure:
7.2 g of (4S)-3-[(3R,2S)-3-(4-Ethoxyphenyl)-3-hydroxy-2-isopropoxypropanoyl]-4-benzyl-1,3-oxazolan-2-one was dissolved in 200 ml of trifluoroacetic acid, 40 ml of triethylsilane was added, and the mixture was stirred for 24 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), to give 7.0 g of (4S)-3-[(2S)-3-(4-ethoxyphenyl)-2-isopropoxypropanoyl]-4-benzyl-1,3-oxazolan-2-one as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].[I-].[Na+]>>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][CH2:14][CH:13]2[C:11]([N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=2)[C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)=[O:12])=[CH:18][CH:19]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(OCCN(C)C)cc32)cc1
Yield: 6.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 110 using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g), 2-chloro-N,N-dimethylethylamine hydrochloride (0.36 g) and sodium iodide (0.51 g) as starting materials, 7-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (36 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([CH3:15])([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:23]#[N:24]>C1COCC1.CCOC(C)=O>[CH3:14][C:6]([CH3:15])([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:2]1[CH2:3][O:4][C:23]([NH2:24])=[N:1]1
Reactant: CC(C)(Cc1ccccc1)CC(N)CO
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(Cc1ccccc1)CC1COC(N)=N1
Reaction time: 17 h
Yield: 54.3 %

Procedure:
To a stirred solution of (RS)-2-amino-4,4-dimethyl-5-phenyl-pentan-1-ol (0.97 g) at r.t. in THF (15 ml) under an argon atmosphere were added K2CO3 (0.78 g) and a solution of BrCN (0.59 g) in THF (10 ml). The mixture was stirred for 17 h. The suspension was diluted with EtOAc and washed with H2O. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on Isolute® Flash-NH2 silica gel from Separtis (gradient: cyclohexane ->CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-4-(2,2-dimethyl-3-phenylpropyl)-4,5-dihydro-oxazol-2-ylamine (0.59 g) as an off-white sticky solid. MS (ISP): 233.2 ([M+H]+))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)cc3)cs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2nc(-c3ccc(Cl)cc3)cs2)c1
Yield: 24.7 %

Procedure:
To a solution of the compound (660 mg) obtained in Example 106a in tetrahydrofuran (5 ml) was added 2N lithium hydroxide aqueous solution (5 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, and adjusted to pH 5-6 with 3N hydrochloric acid. The resulting precipitate was collected by filtration. The obtained solid was dissolved in tetrahydrofuran and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from ethanol to give the title compound (150 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:14]=3[N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[Na+].Br[CH2:36][CH2:37][O:38][CH3:39].C(N(CC)C(C)C)(C)C>C(#N)C.C(=O)(O)[O-].[Na+].O.C(Cl)Cl>[CH3:39][O:38][CH2:37][CH2:36][N:5]1[CH2:4][CH2:3][C:2]([CH2:8][O:9][C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:16]=4[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:14]=3[N:13]=[CH:12][CH:11]=2)([CH3:1])[CH2:7][CH2:6]1
Reactant: CC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCNCC1
Reactant: COCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: COCCN1CCC(C)(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-((4-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (74 mg, 0.16 mmol) in acetonitrile (1.7 mL) was added sodium iodide (26 mg, 0.17 mmol) and 1-bromo-2-methoxyethane (16 uL, 0.17 mmol). The reaction mixture was warmed to 50° C. for 18 hours. The mixture was allowed to cool and then 1-bromo-2-methoxyethane (65 uL, 0.69 mmol) and N,N-diisopropylethylamine (29 uL, 0.16 mmol) were added and the mixture was heated at 50° C. for an additional 4 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL), water (20 mL), and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in dichloromethane) to afford the title compound as an oil, which was used in the next step without any further purification (36 mg, 43%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:36][CH3:37])=[C:20](/[CH:21]=[CH:22]\[CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[C:13]=3[O:12]2)=[N:2]1
Reactant: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C\C1CCNCC1)OC(=Cc1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of tert-butyl 4-((Z)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0387 g, 0.0771 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol) to obtain (Z)-2-[(1H-indazol-3-yl-methylene]-6-methoxy-7-[(Z)-2-(piperidin-4-yl)vinyl]benzofuran-3(2H)-one (0.0108 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH2:34][C:35]([CH2:44][O:45][C:46](=[O:48])[CH3:47])([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:36](Cl)=[O:37])(=[O:32])[CH3:31].C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[C:41]([O:40][CH2:39][C:35]([CH2:44][O:45][C:46](=[O:48])[CH3:47])([CH2:34][O:33][C:30](=[O:32])[CH3:31])[C:36]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:37])(=[O:43])[CH3:42]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCC(COC(C)=O)(COC(C)=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(COC(C)=O)(COC(C)=O)COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 60 °C
Reaction time: 120 h

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (1.05 g, 1.43 mmol) was dissolved in dimethylacetamide (2 ml) and added to trisacetoxymethylacetyl chloride (2.17 g, 7.4 mmol). The mixture was stirred at 60° C. for 5 days, and after cooling the mixture was added to an aqueous solution of sodium hydrogen carbonate (60 ml, 2%). The precipitate formed was filtered off and dissolved in chloroform (90 ml). The organic phase was washed with water (4×40 ml), dried (Na2SO4), and the solvent evaporated. A semisolid residue (1.16 g) was left, which according to MS analysis consisted of the two compounds: 5-(3-Acetoxy-2,2-diacetoxymethyl-propionylamino)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide with MS (ESP, m/e): 1002 ([M]+, 100%) and 5-acetamido-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide with
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O.[OH-].[Na+]>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:10]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1N1CCOCC1
Temperature: 50 °C

Procedure:
Refer to synthesis of (D46) for preparation of 2,6-dichloro-nicotinamide (1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1) (1.85 g, 9.70 mmol) and morpholine (1.69 mL, 19.4 mmol) in anhydrous dimethylformamide (20 mL) was heated to 50° C. for 2.5 h. The reaction was then cooled to room temperature and diluted with 0.1 M NaOH (600 mL) and extracted with ethyl acetate (3×500 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound (2.49 g) as an orange oil, which later solidified upon standing. Compound 6-Chloro-2-morpholin-4-yl-nicotinamide (2) was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) 87.89 (br s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.56 (br s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.67 (br t, J=4.7 Hz, 4H), 3.31 (br t, J=4.7 Hz, 4H).