Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(=O)C>[Zn].C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:23]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
To a suspension of 8.35 g. of activated zinc in 120 ml. of absolute benzene is added at room temperature a solution of 10.3 g. of dibenzo[a,d]cyclohepten-5-one and 8.35 g. of ethyl bromoacetate in 50 ml. of absolute benzene. After about one quarter of said solution has been so added the mixture is heated at reflux until the resulting reaction subsides and then the remainder of the solution is added while maintaining reflux temperatures. After addition is completed the resulting mixture is refluxed for an additional 4 hours. The resulting mixture is then added to dilute acetate acid and extracted 2 times with ethyl acetate. The combined organic phases are washed with water, dried and evaporated in vacuo. The residue is crystallized from diethyl ether/pentane to obtain 5-hydroxy-dibenzo[a,d]cyclohepten-5-acetic acid ethyl ester, m.p. 93°-99° C.
Reaction SMILES: F[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.CCN(C(C)C)C(C)C.[Cl-].[CH3:24][N:25]([CH3:32])[S:26]([CH2:29][CH2:30][NH3+:31])(=[O:28])=[O:27]>CCOC(C)=O>[C:8]([C:3]1[C:2]([NH:31][CH2:30][CH2:29][S:26]([N:25]([CH3:32])[CH3:24])(=[O:28])=[O:27])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:9]
Reactant: CN(C)S(=O)(=O)CC[NH3+]
Reactant: N#Cc1ncccc1F
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCNc1cccnc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm. Bull. 1985, 33: 565-571) (1 g, 8.2 mmol) was placed in a high pressure tube equipped with a stir bar. DMSO (7 mL), Hunig's base (1.57 mL, 9.0 mmol) and 2-[(dimethylamino)sulfonyl]-ethanaminium chloride (1.7 g, 9.0 mmol) were added and the vessel was sealed and heated to 80° C. for 5.5 hours, then stirred at room temperature overnight. The reaction was treated with an additional 0.3 equivalent of Hunig's base and 0.2 equivlanet of the amine salt and heated for 3 hours, but the reaction progressed no further. The mixture was cooled, added to the top of a silica gel column (60 mm by 7 inches) packed in EtOAc and the column eluted with EtOAc. Careful cutting of fractions allowed isolation of the product after evaporation as a clear, colorless oil that solidified upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:43])[CH2:40][C:41]#[CH:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:43][CH:39]([CH2:38][CH3:37])[CH2:40][C:41]#[CH:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCC(O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1OC
Yield: 52.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-hexyn-3-ol (46 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (73 mg, yield 52%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[N:15]([CH2:23][O:24][CH3:25])[C:14]=2[CH:26]=1.C(OCC)C>ClCCl>[CH3:25][O:24][CH2:23][N:15]1[C:14]2[CH:26]=[C:10]([CH2:9][NH:8][C:5](=[O:7])[CH3:6])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COCN1c2cc(CNC(C)=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 ml of acetic anhydride was added to 5 ml of a solution of 350 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in dichloromethane and the resulting mixture was stirred at room temperature for 2 hours. After adding diethyl ether, the precipitate thus formed was taken up by filtration to thereby give 350 mg of the title compound as yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:10]([N:17]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=[C:18]1[S:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)c1cccs1
Reactant: S=C=NCc1ccccc1
Reactant: BrCc1ccccc1
Product: c1ccc(CSc2nnc(-c3cccs3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-thiophencarboxylic acid hydrazide, benzyl isothiocyanate and benzyl bromide as the starting materials. (M+H)+−364.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cccc2ccccc12
Product: Clc1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and naphthalene-1-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 473.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9 L) was added EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306, 2.14 equiv) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv) and the solution was stirred for 20 minutes at room temperature. Then it was cooled to 15-20° C. and cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv) was added and stirred at room temperature. The reaction was monitored by TLC. After 14 hours, since the reaction was not complete and additional cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirring was continued for two hours. DMF was removed under reduced pressure at 50-55° C. To the residue EtOAc (1 L) and water (500 ml) were added and the mixture was stirred for 10 minutes. The mixture was extracted and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layer was washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue EtOAc/dichloromethane /hexane (50 ml/50 ml/50 ml) was added, the mixtue was stirred for 10 minutes, and filtered to provide the product (34.1 g, 65.7%) as an off white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 50/50, 30 min elution) tR 5.53 min, 99.3% purity; MS m/z 360 [M]+; 1H NMR (DMSO-d6, 400 MHz) is consistent with Example 4.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1N2CN3CN(C2)CN1C3.C(O)(=[O:26])C.Cl>C(Cl)(Cl)(Cl)Cl.O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:26]
Reactant: CC(=O)O
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1cccc(OC=C(Cl)Cl)c1

Procedure:
3(2,2-Dichlorovinyloxy)benzyl bromide (2.5 g) was carefully added to a stirred solution of hexamethylene tetramine (2.1 g) in carbon tetrachloride (20 ml) at the ambient temperature. After five minutes the precipitate was collected by filtration and washed with acetone. The solid thus obtained was added to aqueous acetic acid solution (50% by weight, 16 ml) and the mixture refluxed for one hour. A mixture of water (16 ml) and concentrated hydrochloric acid (4.5 ml) was then added and the mixture refluxed for a further 15 minutes. After cooling the mixture was extracted with chloroform, the extracts washed with water (twice), dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure to yield a residue of substantially pure 3(2,2-dichlorovinyloxy)benzaldehyde, identification of which was confirmed by infra-red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH-:18].[K+].[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>O>[CH2:21]([O:20][C:24](=[O:18])/[CH:23]=[CH:16]/[C@H:13]1[CH2:12][CH2:11][C@H:10]([C@H:7]2[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:15][CH2:14]1)[CH3:22]
Reactant: C1CCOC1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/C(=O)OCC)CC2)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 4.5 g of trans-4-(trans-4-propylcyclohexyl)cyclohexanecarboxaldehyde, 5 g of ethyl diethylphosphonoacetate (C2H5O)2PCH2COOC2H5, 1.9 g of potassium hydroxide and 100 ml of tetrahydrofuran was stirred for 15 minutes and then treated with 500 ml of water and subsequently extracted three times with 100 ml of diethyl ether each time. The combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. The residue was purified by chromatography on silica gel with toluene. Recrystallization from acetone gave 1.8 g of pure (E)-3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]acrylic acid ethyl ester with m.p. (C-N) 33° C. and cl.p. (N-I) 76° C..
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([OH:5])[CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])c(O)c1
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc([N+](=O)[O-])c(O)c1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
Thionyl chloride (0.83 mL, 6.6 mmol) was added portionwise to a suspension of (E)-3-(3-hydroxy-4-nitro-phenyl)-acrylic acid (1.05 g, 5.0 mmol) in DCM-DMF (20-2 mL). After stirring the resulting solution at RT for 1.5 hrs, 3-chloro-aniline (2.12 mL, 20 mmol) was added dropwise and the mixture was stirred at RT for additional 2 hrs. Then the reaction mixture was diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was dried over sodium sulphate and evapored. The resulting raw material was purified first by column chromatography (eluant DCM/MeOH), yielding 1.25 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28]([O:27][CH3:26])=[O:29])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: COC(=O)C1CCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)C1CCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(methyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.30 minutes; C23H22C12N4O4 (489.36); mass spectrum: (M−H)−=488/490/492 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.[Li][CH2:14]CCC.CI.O>CCOCC>[Br:12][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([CH3:14])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc2ccc(Br)cc2c1
Solvent: CI
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2ccc(Br)cc2c1
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
Suspension of 2,7-dibromonaphthalene (61.4 g, 0.21 mole) in ether (400 ml) was cooled to −30° C., and n-BuLi (1.6M in hexane, 135 ml, 0.21 mole) was added. Reaction mixture was allowed to warm to room temperature, stirred for additional 2.5 h, cooled to −30° C., and CH3I (13.5 ml, 0.21 mole) was added. Reaction mixture was allowed to warm to room temperature, stirred for additional 16 h, treated by water (100 ml). Organic layer was separated, water layer was extracted by ether (6×100 ml). Combined organic fraction was evaporated, giving practically pure solid product. The yield 38.1 g (82%).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([O:18]CC=C)=[O:17])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N1CCOCC1.O.Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:9]=2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=Cc2cc(Br)ccc2N(CC=C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCN1
Product: C=CCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of allyl 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (224 mg) in tetrahydrofuran (10 ml) were added tetrakistriphenylphosphinepalladium (74 mg) and morpholine (560 mg), and the mixture was stirred under argon atmosphere at room temperature for 2 hours. To the mixture was added water at 0° C., and the mixture was made acidic (pH=4) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, further with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid (198 mg) as yellow amorphous.
Reaction SMILES: Cl[C:2]1[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[N:3]=1.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>COC(C)(C)C>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[NH:3][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]3)=[N:12][C:5]=2[CH:6]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1ncc2c(nc(Cl)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Solvent: COC(C)(C)C
Product: Cn1ncc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
69.7 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one was combined with 153.4 g of t-butyl piperazine-1-carboxylate, and the mixture was stirred and heated to 100° C. under nitrogen atmosphere. When the reaction mixture became easily stirrable, the temperature was raised to 150° C. The mixture was kept at this temperature for one hour. The reaction solution allowed to cool and then suspended in 250 ml of t-butyl methyl ether. The suspended material was collected by filtration. The solid was washed twice with 200 ml of t-butyl methyl ether and three times with 200 ml of water. The solid was again washed twice with 200 ml of t-butyl methyl ether, and dried to give 50.3 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CS(C)=O
Solvent: O
Product: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.12 g, 21.6 mmol) in DMSO (20.5 mL) was added 3-methoxypropylamine (4.40 mL, 43.1 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to give a light yellow brown solid as 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, br. s.), 8.54 (1H, d, J=2.3 Hz), 8.43 (1H, d, J=2.3 Hz), 3.69-3.78 (2H, m), 3.56 (2H, t, J=5.7 Hz), 3.40 (3H, s), 1.96 (2H, dt, J=12.2, 6.2 Hz).
Reaction SMILES: C[O:2][CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.[S:13]1[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[S:13]1[CH:14]=[C:15]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[CH2:3][OH:11])[CH2:16][CH2:17][CH2:18]1.[S:13]1[CH2:18][CH2:17][CH:16]=[C:15]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[CH2:3][OH:2])[CH2:14]1
Reactant: COC(OC)c1cccc(Br)c1
Reactant: O=C1CCCSC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCc1cccc(C2=CCCSC2)c1
Product: OCc1cccc(C2=CSCCC2)c1
Yield: 1 %
Yield: 2 %

Procedure:
534 mg of 3-(tetrahydro-3-hydroxy-3-thiopyranyl)benzaldehyde dimethyl acetal obtained by performing the same reaction as in Referential Example 35 using 3-bromobenzaldehyde dimethyl acetal and tetrahydrothiopyran-3-one as starting materials was dissolved in 5 ml of ethyl acetate, and with stirring under ice cooling, 187 microliters of methanesulfonyl chloride and 553 microliters of triethylamine were added. The mixture was stirred for 30 minutes. The triethylamine hydrochloride was separated by filtration and the solvent was evaporated. The residue was dissolved in 20 ml of benzene, and 373 mg of 90% potassium tert-butoxide was added, and the mixture was stirred at room temperature for 15 hours. Ethyl ether and water were added to the reaction mixture, and the mixture was worked up in a customary manner. The resulting 3-dihydrothiopyranylbenzaldehyde dimethyl acetal was dissolved in a mixture of 3 ml of 1 N HCl and 6 ml of tetrahydrofuran. The solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl ether and water, and worked up in a customary manner. The resulting formyl compound was dissolved in 20 ml of tetrahydrofuran, and 380 mg of lithium aluminium hydride was added. The mixture was stirred for one hour under ice cooling. The reaction mixture was poured into ice water, worked up in a customary manner and purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: hexane/ethyl acetate=2/1] to give 7 mg (yield 2%) of the captioned 3-(3,4-dihydro-2H-thiopyran-5-yl)benzyl alcohol and 4 mg (yield 1%) of 3-(5,6-dihydro-2H-thiopyran-3-yl)benzyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](C3C=CNN=3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O)(=O)C>CN1C(=O)CCC1>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(-c2cc[nH]n2)nc1-c1cccc(O)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(N2CCOCC2)nc1-c1cccc(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Resin bound 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-pyrazolylpyrimidine-5-carboxylic acid (100 mg, 0.055 mmol, 1 eq) was suspended in NMP, and morpholine (144 μL, 144 mg, 1.65 mmol, 30 eq) was added, followed by acetic acid (31 μL, 33 mg, 0.55 mmol, 10 eq). The reaction mixture was shaken at 90° C. overnight. The resin was filtered and washed with DMF, water, MeOH, CH2Cl2, then dried. The resin was treated with 95% TFA/H2O for 1.5 h at room temperature. Filtration and evaporation under reduced pressure afforded 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-morpholin-4-ylpyrimidine-5-carboxylic acid.