Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[C:18]([CH3:28])=[CH:17][C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Yield: 82.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-cyanobenzoic acid (2.14 g) described in Preparation Example 192 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (2.16 g) described in Preparation Example 96, the title compound (3.31 g) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(OC1CCCCC1C(C)(C)C)(=O)C.[H][H]>>[C:1]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccccc1O
Agent: CC(=O)OC1CCCCC1C(C)(C)C
Product: CC(C)(C)[C@H]1CCCC[C@H]1O

Procedure:
A pressurized container fitted with stirrer is charged with 2-tertiary-butylphenol, 2-tertiary-butylcyclohexyl acetate and the catalyst. Hydrogenation is carried out at the chosen reaction temperature and hydrogen pressure. The resulting cis-2-tertiary-butylcyclohexanol is obtained following removal of the catalyst by filtration, decantation or centrifugation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCN(CC)CC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(N)ccc3[nH]c2=O)on1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A flask charged with 6-amino-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (0.027 mg, 0.085 mmol)(Example 52), acetic anhydride (0.01 mL, 0.100 mmol), NEt3 (0.018 mL, 0.13 mmol) and 1 mL of THF was stirred for 6 hrs at 25° C. The title compound was eluted from a 5 g SPE with 100% EtAc to give 0.015 g (50%) of a white solid. 1H NMR (400 MHz, CDCl3) 12.30 (s, 1H), 8.06 (s, 1H), 7.72 (m, 1H), 7.36 (m, 5H), 7.14 (m, 2H), 6.36 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C21H17N3O3 359.1, found 360.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:10].C1C=C[NH+]=CC=1.[Br:17][Br-]Br.C(OCC)C>C(O)(=O)C>[BrH:17].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cnccn1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CBr)c1cnccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of acetylpyrazine (10 g, 81.88 mmol) in acetic acid (70 mL) is added hydrogen bromide (38% acetic acid solution, 16 mL) followed by pyridinium bromide perbromide (28 g, 83.17 mmol) which is added in a single portion. The reaction is stirred at room temperature for approximately 1.5 hours. A suspension is formed during this time. Diethyl ether is added (500 mL) and the resulting precipitate is collected by filtration. The isolated product is washed with acetonitrile and diethyl ether and is dried under vacuum to give a pale brown solid (23.2 g, quantitative yield). 1H NMR (d6-DMSO) δ 9.19 (1H, m), 8.95 (1H, m), 8.84 (1H, m), 5.02 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5]Br.[C-:14]#[N:15].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CC#N
Reaction time: 0.17 h

Procedure:
To a solution of 2-methoxy-5-nitrobenzyl bromide (984 mg) in dimethylsulfoxide (5 mL) was added sodium cyanide (216 mg) and the mixture was stirred at 80 degrees for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methanesulphonyl chloride (2.4 ml) was added dropwise to an ice-cooled solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butan-1-ol (8.13 g) (see Preparation 28) and triethylamine (5.32 ml) in dichloromethane (100 ml) under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. and then 90 minutes at room temperature before being washed twice with water. The organic phase was separated, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give the crude product. This was chromatographed on silica gel eluting with 95:5, by volume, dichloromethane:diethyl ether to give 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (8.85 g) as a yellow oil and as a mixture of diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][NH:31][C:28]2=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][N:31]([C:19]3[C:14]4[C@H:13]([CH3:21])[CH2:12][C@@H:11]([O:10][C:8](=[O:9])[C:7]5[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)[C:15]=4[N:16]=[CH:17][N:18]=3)[C:28]2=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate. LCMS (APCI+) m/z 339.1 [M+H−Boc-pNO2 benzoic acid]+; Rt=4.74 min.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1N)[C:9]([OH:11])=[O:10].O.Cl>C(O)CCCC>[N:1]1[C:2](=[O:3])[N:4]=[C:13]2[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[CH:6][C:14]=12
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: CCCCCO
Product: O=C1N=c2ccc(C(=O)O)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Urea (1.20 g, 0.0200 mol) and 3,4-diaminobenzoic acid (3) (3.04 g, 0.0200 mol) in pentan-1-ol (10 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. The heating was discontinued after 4 hours and on cooling to room temperature, water (30 mL) was added. The pH was adjusted to 1 with conc. HCl. The resultant dark solid was filtered off, washed with further water (2×20 mL) and dried to give 3.00 g (84% yield) of benzimidazol-2-one-5-carboxylic acid (4) as a black powder,
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)(O)[O-].[Na+].COCCOCCOC.[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42](O)[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:29]1([C:35]2[NH:44][C:38]3[N:39]=[CH:40][N:41]=[C:42]([SH:2])[C:37]=3[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reaction time: 1 h
Yield: 94.8 %

Procedure:
After adding 6.19 g of phosphorus pentasulfide, 6.24 g of sodium bicarbonate and 25 ml of diglyme to 2.45 g of the 6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 1 hour, an additional 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate were added and the mixture was stirred for 1 hour. There were further added another 3 g of phosphorus pentasulfide and 3 g of sodium bicarbonate, and the mixture was stirred for 1 hour. It was then returned to room temperature, water was added, the mixture was stirred for 10 minutes, and the precipitated crystals were filtered out, washed with water and dried to obtain 2.5 g of the title compound.
Reaction SMILES: O[CH2:2][C:3]1(CO)[CH2:8][C:7]2[CH:9]=[CH:10][S:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[CH3:41][O:42][CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][CH3:49]>C1COCC1>[CH3:41][O:42][CH2:43][CH2:44][N:45]([CH2:2][C:3]1[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[S:5](=[O:13])(=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH2:46][CH2:47][O:48][CH3:49]
Reactant: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Reactant: COCCNCCOC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN(CCOC)CC1=Cc2ccsc2S(=O)(=O)N1Cc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step C (1.60 g, 4.75 mmol) and triethylamine (1.44 g, 14.2 mmol) in anhydrous THF (100 mL) at ambient temperature was added methanesulfonic anhydride (1.24 g, 7.13 mmol). After 1 h, the reaction mixture was divided into two equal portions; to one of these portions was added bis(2-methoxyethyl)amine (6 mL). The mixture was stirred for 72 h, evaporated to dryness and the residue extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to a residue which was purified by column chromatography (silica, 20-30% ethyl acetate/hexane) to give an oil (0.71 g) which solidified upon standing: mp 75°-77° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH2:43])=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH:43][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
2-Phenylacetic acid (592 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide (606 mg, 80.1% yield) was obtained as a solid.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]1[O:12][CH2:11][C@@H:9]([OH:10])[C@H:7]1[OH:8].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:8][CH:7]1[CH:9]([O:10][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:11][O:12][CH2:6]1
Reactant: C[Si](C)(C)Cl
Reactant: O[C@@H]1COC[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OC1COCC1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
TMSCl (8.0 mL, 63.32 mmol) was added dropwise to a solution of 1,4-anhydroerythritol (3.0 g, 28.81 mmol), triethylamine (9.2 mL, 66.0 mmol) and DMAP (few crystals) in dichloromethane (200 mL) at 0° C. The reaction was allowed to slowly warm to room temperature over 1 h and then stirred for an additional 3 h. The solid was filtered and the filtrate concentrated to give a solid. The solid was then filtered through a short silica gel column eluting with 33% hexanes in ethyl ether. Removal of solvents under reduced pressure provided 3,4-bis-trimethylsilanyloxy-tetrahydro-furan (7.7 g, ˜100%) as a colorless liquid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:27][C:26](=[O:28])[CH:25]=[CH:24][NH:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([N:23]1[CH:24]=[CH:25][C:26](=[O:28])[CH2:27][CH:22]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COc1cc(I)c(CC(=O)O)cc1OC
Reactant: O=C1C=CNC(c2ccccc2)C1
Product: COc1cc(I)c(CC(=O)N2C=CC(=O)CC2c2ccccc2)cc1OC

Procedure:
1-[2-(2-Iodo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one was prepared by reacting (2-iodo-4,5-dimethoxy-phenyl)-acetic acid with 2-Phenyl-2,3-dihydro-1H-pyridin-4-one following the procedure of step 3 of Example 1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1.CN1C(=O)CCC1>C1COCC1>[Br:16][C:17]1[C:22]([CH:23]=[CH:24][C:25]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Br)n1
Yield: 32.7 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (116 mg, 0.454 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 129 mg) DMTMM (1.0 eq, 126 mg) and NMP (1.2 eq, 60 μl) in THF to give the title compound (72 mg, 32.8%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: [F-]
Reactant: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2c(OC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 67.1 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-cyclopropoxyisoquinolin (0.24 g, 1.01 mmol) in DMSO (2 ml) was added cesium fluoride (0.38 g 2.52 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.15 g 67%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2].[I:15]Cl>C(Cl)Cl.CCOCC>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:15])[CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1OC(C)C
Reactant: ClI
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1cc(I)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-isopropoxyphenyl acetate (10 mmol) in CH2Cl2 at 0° C., iodine monochloride (1.0 M in CH2Cl2, 11.0 mL) was added dropwise in 20 min. The mixture was stirred at 0° C. for 2.0 h, diluted with ether, washed with saturated Na2S2O3 and brine. The organic extract was dried over MgSO4 and evaporated to give 5-iodo-2-isopropoxyphenyl acetate as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][O:6][C:7]1[C:8]([CH:23]=[CH2:24])=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH2:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:3][CH:2]([CH3:1])[CH3:33])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)[CH3:24]
Reactant: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 40.1 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.15 g, 0.332 mmol) and palladium on carbon (0.075 g, 0.070 mmol) in MeOH (3 mL) and ethyl acetate (3 mL) was stirred at RT under a balloon of hydrogen gas for 24 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC (60% ethyl acetate and petroleum ether) to afford (S)-tert-butyl (1-((9-ethyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan 2-yl)carbamate (0.11 g, 0.133 mmol, 40% yield) as a yellow semi solid. LC/MS (ESI) m/e 454.4, [(M+H)+, calcd for C26H36N3O4, 454.3]; LC/MS retention time (method D): tR=0.96 min.
Reaction SMILES: CC(C)(C)C(OC[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10]([S:17][CH3:18])=[N:11][C:12]=2[Cl:16])=O.[OH-].[Na+]>CC(O)C.C1COCC1>[Cl:16][C:12]1[N:11]=[C:10]([S:17][CH3:18])[N:9]=[C:8]2[C:13]=1[NH:14][CH:15]=[N:7]2
Reactant: CSc1nc(Cl)c2ncn(COC(=O)C(C)(C)C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CSc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
To a solution of 6-chloro-2-methylthiopurin-9-ylmethyl 2,2-dimethylpropionate (82) (0.314 g, 1 mmol) in i-PrOH (10 mL) and THF (25 mL) was added 2N aq NaOH (2 mL) and the resulting reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (AcOEt/petroleum ether=3/7) which afforded 83 (0.112 g, 56%): 1H NMR (DMSO-d6, 300 MHz) δ 8.54 (s, 1H), 2.58 (s, 3H) MS (m/e) (positive-FAB) 200.9 (M+1)+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([C:20]([OH:22])=O)=[C:5]([C:15](OCC)=[O:16])[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[NH2:24][NH2:25]>C(O)C>[OH:2][C:3]1[C:4]2[C:20](=[O:22])[NH:25][NH:24][C:15](=[O:16])[C:5]=2[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc(-c2ccccc2)c(O)c1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(O)c(-c3ccccc3)ncc12

Procedure:
A mixture of 2 g. ethyl 5-hydroxy-6-phenylpyridine3,4-dicarboxylate. hydrochloride, 40 ml ethanol and 4 ml hydrazine hydrate was refluxed for 4 hours. After cooling, the pale yellow crystals were recovered by filtration, suspended in 20 ml of water and made acid with dilute hydrochloric acid. The crystals were recovered by filtration, rinsed with water and dried. The procedure provided 1.2 g of 8-hydroxy-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)-dione, melting point: more than 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[N:10]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)nn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
6-(Methoxycarbonyl)-3-methyl-1H-indazole (0.40 g, 2.1 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was ice-cooled. Sodium hydride (85 mg, 60% suspension in oil, 2.1 mmol as NaH) was added and the mixture was stirred at 0° C. for 30 min. 2,4-Dichlorobenzyl chloride (0.45 g, 2.31 mmol) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was extracted with ethyl acetate/water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystalline residue was separated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to give the objective compound (0.54 g, 74%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.C([Li:21])CCC.CCCCCC>O1CCCC1>[C:1]1([S:7][CH2:8][Li:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: [Li]CCCC
Agent: C1CN2CCN1CC2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]CSc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 5.4 g (44 mmol) of thioanisole and 4.89 g (43.6 mmol) of 1,4-diazabicyclo[2,2,2]octane in 44 ml of tetrahydrofuran was placed in an oven-dried flask and cooled to 0° C. A 2.5 M solution of butyl lithium in hexane (17.4 ml, 43.6 mmol) was added with stirring and the mixture allowed to warm to room temperature and react for about 1 hour to form phenylthiomethyl lithium. A solution of 3.14 g (8.71 mmol) of 1-(2-methoxymethoxyphenyl)-1-(3,4-dimethoxy-2-methoxymethoxyphenyl)ethene in tetrahydrofuran was added and the mixture heated to reflux with stirring under an argon atmosphere After 10 hours another 21 8 mmol of phenylthiomethyl lithium was prepared and added to the mixture and refluxing was continued overnight. The mixture was then cooled and poured into 200 ml of 5 percent aqueous sodium hypochlorite solution and 200 g of ice and 150 ml of ether added. The organic phase was separated, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 6.61 g of an oil. This was purified by silica gel chromatography (80 mm×3" filter funnel), eluting with hexane containing ever increasing amounts of ether to obtain 1.16 g of the title compound as an oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.