Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C.O1CCCC1>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (10.13 g) and ethanolamine (3.52 ml) in a mixture of ethanol (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours. Ethanolamine (3.35 ml) was added and the mixture was stirred at 50° C. for 1 hour. Then, ethanolamine (3.35 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained solid was washed with isopropanoyl, collected by filtration, and dried under reduced pressure to give the title compound (7.25 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: COc1cc(N)c2ncccc2c1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(OC)cc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 73 mg (0.417 mmol) of 8-amino-6-methoxyquinoline was added. The resulting mixture was stirred at room temperature for two hours and the final product was collected by filtration and washed with diethylether to yield the title compound (88 mg, 76.5% yield).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[CH2:42]([CH2:44][NH2:45])[OH:43]>C(Cl)Cl>[OH:43][CH2:42][CH2:44][NH:45][C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[C:12]([NH:11][CH:8]([CH3:9])[CH3:10])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:19][CH2:20]2)=[O:25])=[N:27][CH:28]=1)=[O:31]
Reactant: NCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (0.54 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid (1.3 g) in methylene chloride (40 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.45 ml) at 0° C.˜5° C., the reaction mixture was stirred at 5° C. for 2 hours. With the addition of triethylamine (0.6 ml) and ethanolamine (0.25 ml), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was washed with aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with ethanol and isopropyl ether to give a desired compound of 1.2 g (yield: 83%).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2)(=O)C1C=CC=CC=1.N>CO>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:19](=[O:23])[NH:18][C:17]([NH2:24])=[N:16][C:15]1=2
Reactant: Nc1nc2c(ncn2COCCOC(=O)c2ccccc2)c(=O)[nH]1
Agent: N
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Yield: 78.2 %

Procedure:
9-(Benzoyloxyethoxymethyl)guanine (0.58 g) and methanol (80 ml) saturated with ammonia were heated in a bomb at 80° C. for 16 hours. The reaction mixture was removed from the bomb and the solvent evaporated under reduced pressure. The residue was thoroughly washed with ether and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.31 g., 75% of theoretical), m.p. 256.5°-257° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:30])[C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=1)[CH2:25][C:26]([F:29])([F:27])[F:28]
Reactant: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reaction time: 0.33 h

Procedure:
To a solution of crude 2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)-4,4,4-trifluorobutanamide (180 mg) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred for 20 min. HOAc (0.5 mL) was added. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 437.3 (M+H); UV 202.2, 224.1, 295.2 nm; t 0.482 min.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:13]([O:14]CC2C=CC=CC=2)[C@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[CH:38]=[C:37]([F:39])[C:35](=[O:36])[NH:34][C:32]1=[O:33])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl.O>[C@@H:10]1([N:31]2[CH:38]=[C:37]([F:39])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[O:11][C@@H:12]([CH2:22][OH:23])[C@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1F
Agent: ClB(Cl)Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)cc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To a solution of 24 (1.0 g, 1.87 mmol) in CH2Cl2 (50 ml), at -78° C. under nitrogen atmosphere, 1M solution of BCl3 (20 ml, 20.57 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for four hours, a 1:1 mixture of CH2Cl2 /MeOH (50 ml) was added and the reaction mixture was brought to room temperature and the solvents were evaporated to dryness. The residue was coevaporated with MeOH (25 ml) 5 times. The residue obtained was dissolved in water and washed with CHCl3 (2×50 ml). The water layer was evaporated to give a white solid which was crystallized from EtOH/ether to give the pure 25 (0.41 g, 83%) as white crystals: m.p. 150° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].C(N(CCCC)CCCC)CCC.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=[CH2:40].[OH-].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1/[CH:39]=[CH:40]/[C:8]1[CH:7]=[CH:6][C:5]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:16]
Reactant: C=Cc1ccccc1F
Reactant: CCC(=O)Nc1ccc(Br)cc1C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(/C=C/c2ccccc2F)cc1C(=O)O
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-bromo-2-propionylamino-benzoic acid methyl ester (1.0 g, 3.50 mmol), potassium carbonate (532 mg, 3.85 mmol), tri-n-butyl amine (0.917 mL, 3.85 mmol) and PdCl2(PPh3)2 (35 mg, 0.05 mmol) in DMF (20 mL) was added 2-fluoro-styrene (0.50 mL, 4.2 mmol). The reaction mixture was heated to 150° C. and left at this temperature for 18 hours. after which it was allowed to reach room temperature. Water (10 mL) and 5M NaOH (2 mL) were added and the temperature was once again raised to 150° C. After one hour at this temperature the reaction mixture was allowed to reach room temperature. Water (50 mL) was added and the mixture was filtered by suction through Celite. The filtrate was acidified with 5M HCl, the product collected by filtration and re-crystallised from ethanol (511 mg, 47%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: COc1c(N2CCCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.85 g of piperidine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, and separated crystals were filtered and dried to obtain 1.44 g of the objective compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:7]=1)[O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([O:35][CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:34][CH2:33]2)=[CH:44][CH:43]=1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCN)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3OCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
1.06 g (3.50 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2 mmol)) of 2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml (5.19 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:42])[NH2:27])=[CH:22][CH:21]=3)[CH3:19])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=O)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[CH2:28][CH:27]([N:29]2[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]2)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:25]3[CH2:26][CH:27]([N:29]4[CH2:34][CH2:33][NH:32][C:31](=[O:35])[CH2:30]4)[CH2:28]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: O=C1CN(C2CNC2)CCN1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4n3C3CCCCO3)C2)CCN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A mixture of 2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (1.06 g, 3.01 mmol) and 4-azetidin-3-ylpiperazin-2-one (560 mg, 3.61 mmol) in DCE (60 mL) and DMF (20 mL) was allowed to stir at r.t. for 10 min before the addition of 4 Å powdered molecular sieves (3.0 g) followed by sodium triacetoxyborohydride (1.28 g, 6.04 mmol). The resulting mixture was allowed to stir for 64 h then filtered through Celite® which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue dissolved in EtOAc and washed with NaHCO3, H2O and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo affording the title compound as a yellow gum (997 mg, 67%). LCMS (method A): RT 2.19 and 2.11 min [M−C5H9O+H]+ 407.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:26]2[CH2:27][CH2:28][C:23]([OH:22])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[CH2:24][CH2:25]2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCCNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Yield: 28.4 %

Procedure:
A mixture of 4-benzyloxy-N-(3-chloro-propyl)-benzamide (0.5 g, 1.64 mmol), ), 4-hydroxy-4-(4-methyl-benzyl)-piperidine (0.34 g, 1.65 mmol), potassium carbonate (0.45 g, 3.29 mmol) and 2-butanone (10 ml) was stirred at 60° C. for 48 h. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride methanol from 95:5 to 9:1) to give 4-benzyloxy-N-[3-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-propyl]-benzamide (220 mg, 28%) as light yellow solid. MS: me/e =473 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(NCCCN3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-morpholinopropylamine according to general procedure 1 providing the amino compound (1.30 g, 59%) as an orange oil; Rf=0.66 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.54 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.47 (d, J=9.7 Hz, 1H), 3.71-3.69 (m, 4H), 3.42 (t, J=6.9 Hz, 2H), 2.51-2.48 (m, 6H), 1.92-1.89 (m, 2H); ES-MS: (M+H)=340, 342 m/z.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=CC=C[C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[CH3:56][N:57]1C=C(S(Cl)(=O)=O)C=[N:58]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[N:58][N:57]([CH3:56])[CH:27]=3)(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cnn(C)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 58.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g, 2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d, J=6.8, 6H). MS (ES+): 475 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[CH:15]1[C:20]2([C:28]3[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:30])[CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH2:18][C:17](=[O:38])[NH:16]1)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:29][C:25]1[CH:24]=[C:23]2[NH:22][C:21](=[O:30])[C:20]3([CH:19]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[CH2:18][C:17](=[O:38])[NH:16][CH:15]3[C:9]3[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=3[O:7][CH2:6][CH2:5][OH:4])[C:28]2=[CH:27][CH:26]=1
Reactant: CC(=O)OCCOc1ccc(C)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[2-(2-acetoxy-ethoxy)-5-methyl-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.29 mmol) prepared in example 128c in tetrahydrofuran (30 mL) and methanol (10 mL) was added sodium hydroxide aqueous solution (1N, 10 mL). the reaction mixture was stirred at room temperature for 3 h, then neutralized to “pH” 7 by aqueous HCl. The mixture was then extracted with ethyl acetate. The organic layer was separated, concentrated, and purified by chromatography (EtOAc:MeOH=19:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-methyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (70 mg, 47%)
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.C1C=CC=CC=1.[C:13]1([CH3:19])[CH:18]=C[CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:3]1([CH3:5])[CH:18]=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:16])[CH:2]=1
Reactant: OCC(O)CO
Reactant: Cc1ccccc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(C)c1

Procedure:
Further, the insulating liquid can include a known liquid as the insulating liquid in addition to the fatty acid triglyceride as described above. Specifically, there can be cited silicone oil such as KF96, KF4701, KF965, KS602A, KS603, KS604, KF41, KF54, FA630 (produced by Shin-Etsu Chemical Co., Ltd.), TSF410, TSF433, TSF434, TSF451, TSF437 (produced by Momentive Performance Materials Inc.), or SH200 (produced by Dow Corning Toray Co., Ltd.), aliphatic hydrocarbon such as TSOPAR-E, ISOPAR-G, ISOPAR-H, ISOPAR-L (produced by Exxon Mobil Corp.), Cosmo White P-60, Cosmo White P-70, Cosmo White P-120 (produced by Cosmo Oil Lubricants Co., Ltd.), Dyna Freshia W-8, Daphne Oil CP, Daphne Oil KP, Transformer Oil H, Transformer Oil G, Transformer Oil A, Transformer Oil B, Transformer Oil S (produced by Idemitsu Kosan Co., Ltd.), Shellsol 70, Shellsol 71 (produced by Shell Oil Company, Ltd.), Amsco OMS, Amsco 460 solvent (produced by American Mineral Spirits Company, Ltd.), low-viscosity/high-viscosity liquid paraffins (produced by Waco Pure Chemical Industries, Ltd.), octane, isooctane, decane, isodecane, decalin, nonane, dodecane, isododecane, cyclohexane, cyclooctane, cyclodecane, a resolvent of the fatty acid triglyceride such as fatty acid monoglyceride, fatty acid diglyceride, glycerine, or a fatty acid, a synthetic esters liquid such as Prifer 6813 (produced by UNIQUEMA), benzene, toluene, xylene, mesitylene, fatty acid monoester, and so on, and one species or a combination of two or more species out of these compounds can be used.
Reaction SMILES: C(=O)([O-])OC.COC(O[C@H:11]1[CH2:16][CH2:15][C@H:14]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:12]12[CH3:13])[C@:25]1([CH3:26])[C@H:20]([CH2:21][C:22](=[O:30])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)=O.N#N>C1(C)C=CC=CC=1>[CH3:13][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([CH2:18][CH2:19][C@@H:20]4[C@:25]3([CH3:26])[CH2:24][CH2:23][C:22](=[O:30])[CH2:21]4)[C@@H:14]1[CH2:15][CH:16]=[CH:11]2
Reactant: COC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 85.4 %

Procedure:
This synthesis is depicted in FIG. 1. A solution of the methyl carbonate, 17β-methoxycarbonyloxy-5α-androstan-3-one (II) (9.6 g, 27.6 mmol) in toluene (200 ml) was pyrolyzed (b) in a Pyrex glass column (l=10 m, φ=9 mm) at 480° (N2 stream ca. 11 ml/min) at a rate of ca. 1 g/h. The crude product (collected in two liquid N2 -cooled traps) was washed with sat. aq. NaHCO3 - and NaCl-solution, dried (Na2SO4) and evaporated. The residue (7.24 g, 97%) was recrystallized from PE at 0° to give 6.42 g (87%) of 1. An analytical sample was recrystallized from acetonitrile at RT. M.p. 142°-144°, [a]D =+35.6° (c=1.15) ([2]: m.p. 140°-141°, [a]D17 =+38° (c=2.08)). - IR. (CDCl3): 1710s, 1595w. - 1H-NMR. (360 Mhz): 0.79 (s, 3 H); 1.05 (s, 3 H); 5.70 (m, 1 H); 5.84 (m, 1 H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:10]=2)([O:3]CC)=[O:2]>C(O)C.[OH-].[Na+]>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)c1cnc2cc(C3CCCCC3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2cc(C3CCCCC3)ccc2c1O

Procedure:
A suspension of 15 g of 3-carboethoxy-4-hydroxy-7-cyclohexyl-quinoline in 150 ml of ethanol and 150 ml of 2 N sodium hydroxide solution is boiled under reflux for 7 hours. It is then evaporated to dryness, the residue is dissolved in ethanol-water and the solution is adjusted to pH value 7 with 2 N hydrochloric acid. The crystalline residue thereby produced is filtered off and thoroughly washed with water. 4-Hydroxy-7-cyclohexylquinoline-3-carboxylic acid thus obtained, melts at 241°-243°C (evolution of gas).