Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:32](=[O:33])[C:31]4[C:30]5[C:25](=[CH:26][C:27]([C:34]#[N:35])=[CH:28][CH:29]=5)[NH:24][C:23]=4[C:22]([CH3:37])([CH3:36])[C:21]=3[CH:38]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40].O1CCOCC1>O>[ClH:40].[CH3:36][C:22]1([CH3:37])[C:23]2[NH:24][C:25]3[C:30](=[CH:29][CH:28]=[C:27]([C:34]#[N:35])[CH:26]=3)[C:31]=2[C:32](=[O:33])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14](=[O:39])[N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:38][C:21]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2cc(OCC(=O)N3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound A9-15-1, 20 mg) was added with 4 N hydrochloric acid and dioxane solution (1 ml), and stirred in an water bath at 10° C. for 4 hr. Water was added to the reaction solution and the resulting precipitates were filtered and dried to obtain the title compound (15 mg, white powder).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
To a suspension of ethyl 5-benzyloxyindole-2-carboxylate (21.9 g, 74.0 mmol) in DMF (30 mL) was added dropwise over 10 min a solution of bromine (11.83 g, 74.0 mmol, 3.8 mL) in DMF (40 mL). After stirring an additional 20 min at room temperature, the solution was partitioned between 3 N HCl and ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, water and saturated brine, then dried (MgSO4), filtered and concentrated to leave a white solid. The solid was recrystallized from ethyl acetate to provide the title compound (19.6 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.96 (br s, 1H), 7.52-7.30 (m, 6H), 7.15-7.10 (m, 2H), 5.14 (s, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[Li]CCCC.[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[O:24][N:23]=2)=[N:20][CH:21]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]([CH:27]([OH:28])[CH2:1][C:2]3[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=3)=[C:25]([CH3:29])[O:24][N:23]=2)=[N:20][CH:21]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: Cc1onc(-c2ccc(F)cn2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1C(O)Cc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (1.15 g, 8.05 mmol) in THF (67 mL) at −70° C. and under argon was added BuLi (1.6M in hexanes, 10.06 mL, 16.1 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde (1.66 g, 8.05 mmol) in THF (24 mL) was added dropwise. After 3 h the reaction mixture was quenched with citric acid solution (5%, 50 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by trituration (ethyl acetate) afforded the title compound (1.85 g, 66%) as a light yellow solid. MS: m/e=348.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]#[CH:3].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH2:1][C:2]#[CH:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: C#CCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: C#CCON=C(C(=O)CCl)C(=O)OCC
Yield: 73.7 %

Procedure:
Ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g.), acetic acid (81 ml.) and sulfuryl chloride (50.2 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 4-chloro-3-oxo-2-propargyloxyiminobutyrate (syn isomer, 61.6 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>O1CCCC1.[Pt]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CC(=O)NCC=C1CCc2c(Cl)cc3nn(C)cc3c21
Agent: [Pt]
Solvent: C1CCOC1
Product: CC(=O)NCCC1CCc2c(Cl)cc3nn(C)cc3c21
Temperature: 25 °C
Reaction time: 7 h
Yield: 29.1 %

Procedure:
To a solution of N-[2-(5-chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]acetamide (79.5 mg, 0.274 mmol) in tetrahydrofuran (5 mL) was added 5% platinum-activated carbon (32 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→25/75), liquid chromatography (water/acetonitrile=90/10→0/100) and recrystallization (ethyl acetate/hexane) to give the title compound (23.3 mg, yield 29%).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1
Reactant: CCOC(=O)c1cn(CO)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.23 g of 1-(hydroxymethyl)-3-(trifluoromethyl)-4-ethyoxycarbonyl-1H-pyrazole was dissolved to 30 ml of dichloromethane. 1.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 2.38 g of 1-(chloromethyl)-3-(trifluoromethyl)-4-ethoxycarbonyl-1H-pyrazole.
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](OC)=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].NC1C=CC([C@H]2CC[C@H](C(C)(C)[C:39]([O:41][CH3:42])=[O:40])CC2)=CC=1>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:39]([O:41][CH3:42])=[O:40])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: COC(=O)C1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1
Product: COC(=O)CC1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1

Procedure:
Prepared following the method of Intermediate 111 part iv). 1H NMR δ 1.23-1.44 (m, 2H), 1.66-1.79 (m, 2H), 1.77-1.93 (m, 1H), 2.16 (s, 3H), 2.30 (d, 2H), 2.59-2.76 (m, 2H), 3.22-3.40 (m, 2H), 3.56 (s, 3H), 4.52 (s, 2H), 7.88 (d, 1H), 8.46 (d, 1H), 10.14 (s, 1H), 10.51 (s, 1H). MS m/e MH+ 350.21.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2].Br[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[F:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[F:31][C:22]1[C:21]([C:8]2[CH:7]=[CH:6][C:5]([NH2:19])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:26]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: Fc1cccc(C(F)(F)F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (264 mg, 1.00 mmol, as prepared in Example 17, step A) and 2-bromo-1-fluoro-3-trifluoromethyl-benzene (243 mg, 1.00 mmol) in DME (5 mL) and 2 M aqueous Na2CO3 (4 mL, 8 mmol) was degassed via sonication, placed under argon and treated with Pd (PPh3)4 (115 mg, 0.100 mmol). The resulting mixture was heated at 80° C. for 16 h and allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (10 mL) and washed twice with water (10 mL). The aqueous layer was extracted with additional EtOAc (10 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica (EtOAc/hexanes, 0:100 to 50:50, v/v) to yield 6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl-amine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.N1C=CC=CC=1>>[OH:1][C:2]1[C:3]([CH:4]=[O:5])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[C:9]=1[CH:17]=[CH:16][C:15]([CH3:19])([CH3:14])[O:10]2
Reactant: CC(C)=CC=O
Reactant: O=Cc1c(O)cc(O)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: CC1(C)C=Cc2c(cc([N+](=O)[O-])c(C=O)c2O)O1
Reaction time: 18 h

Procedure:
A solution of 2,4-dihydroxy-6-nitro-benzaldehyde (10.61 g, 58 mmol) in Me2CO (6 mL) is added during a 5.5 h period to a stirring solution of 3-methyl-but-2-enal (4.00 g, 29 mmol) in pyridine (2.29 g, 2.34 mL, 29 mmol) at 120° C. After completion of addition heating is continued for an additional 18 h. The Me2CO is evaporated and the pyridine is removed by azeotrope distillation with toluene to afford a crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to afford 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([OH:14])=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([OH:14])=[O:13])=[CH:20][CH:19]=2)(=[O:22])=[O:23])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In the same manner as Example 2, 0.60 g (4 mmol) of 4-carboxybenzaldehyde, 0.80 g (4 mmol) of 4-carboxybenzenesulfonamide and 15 mg of TsOH in 80 mL of chlorobenzene under nitrogen were heated to provide 80% of SULF-5 as a light tan powder: IR (Nujol) 3400-2600 (br), 3082, 1688, 1614, 1160 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ9.17 (s, 1), 8.2-7.8 (m, 8).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][OH:14])[CH:9]=2)[CH:4]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[Cl-].[NH4+]>CN(C=O)C.N1C=CN=C1>[Si:15]([O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][OH:14])[CH:9]=2)[CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc2cc(CO)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
The compound (3.41 g) obtained in Example 121-1 was dissolved in anhydrous DMF (200 ml). Then, t-butyldimethylsilyl chloride (2.73 g) dissolved in imidazole (1.48 g) and anhydrous DMF (50 ml) was dropped in this solution, and the whole was stirred overnight at room temperature. After completion of the reaction, the solution was added with a saturated aqueous ammonium chloride solution and stirred. The solution was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution. Then, the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform), thereby obtaining the subject compound (2.68 g) as a white solid.
Reaction SMILES: C(O)(=O)C(O)=O.C([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.C(O)(=O)C>[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1
Reactant: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Yield: 105.4 %

Procedure:
A stirred suspension of N-[(1-benzyl-4-piperidyl)methyl] 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole-10-carboxamide oxalate salt (E20, 2.25 g, 0.0046 mole) in ethanol (100 ml) and glacial acetic acid (4 ml) was hydrogenated over 10% Pd--C (0.8 g) at atmospheric pressure and 45° C. for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The majority of the product was in the solid which had been filtered off. This material was shaken with concentrated potassium carbonate solution (50 ml) and chloroform (50 ml) together with the residue from the filtrate. The mixture was filtered, the chloroform layer separated and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a white solid (1.52 g, 100%). This was recrystallised from chloroform/60-80 petrol mp 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:27])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)c2ccc3c(c2)N(C)C(=O)CO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (5.9 g, 17 mmol) in tetrahydrofuran (380 ml) was added sodium hydride (60% dispersion in mineral oil, 0.72 g, 17.9 mmol). The mixture was stirred at room temperature for 1.5 h and then placed in an ice bath. A solution of methyl iodide (2.54 g, 17.9 mmol) in tetrahydrofuran (15 ml) was added dropwise (5 min) The ice bath was removed and the mixture was stirred at 35° C. for 3.5 h. The reaction mixture was poured on ice-water and extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, heptane/EtOAc 2:1) to give the title compound (3.3 g) as a light yellow foam. MS (m/e)=360.2 [M+H+].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27](Br)[C:22]2=[N:21][CH:20]=1>CCO>[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=3)[C:22]2=[N:21][CH:20]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
p-Phenetidine (0.38 ml, 2.9 mmol) and triethylamine (0.8 ml, 5.8 mmol) were added to a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.83 g, 2.67 mmol) from 1a in EtOH (10 mL). The mixture was heated to 80° C. and stirred for 16 hrs. The solution was then concentrated in vacuo to give crude 3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:7][CH2:6]1.[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[OH:18])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:6][CH:5]([OH:7])[CH2:4][CH2:3][CH2:2][CH3:1])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCCCC1CO1
Reactant: CC(C)(C)C1CCCCC1O
Product: CCCCC(O)COC1CCCCC1C(C)(C)C
Yield: 125.2 %

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 19.2 g (0.192 mol) of 1,2-hexeneoxide was used instead of 11.1 g (0.192 mol) of propyleneoxide, 12.9 g of 2-tert-butylcyclohexanol and 26.5 g of 1-(2-tert-butylcyclohexyloxy)-2-hexanol (cis:trans=8:2) (bp. 116° to 117° C./1 mm Hg) were obtained in a 54% yield. Then, the cis-trans isomers of 1-(2-tert-butylcyclohexyloxy)-2-hexanol were separated from each other in the same manner as described in Example 1.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[O:12]=[S:10]1(=[O:11])[C:3]2[C:2](=[CH:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=2)[C:15]2[C:14](=[C:23]3[C:18](=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13]1
Reactant: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 4.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-cyano-N-quinolin-8-yl-benzenesulfonamide (Intermediate 278) (350 mg, 1.08 mmol), t-butyl nitrite (0.19 ml, 1.62 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (15 mg, 4%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(S(N)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 1-ethanesulfonylpiperazine (1.0 g) in dioxane (10 ml) was added sulfamide (0.51 g). The reaction was then heated at 100° C. for 24 h. The reaction was allowed to cool before being concentrated in vacuo. The residue was stirred in Et2O for 4 h and the mixture filtered to give the product as a white solid. Yield: 1.3 g.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:24]([O:23][C:21]([N:19]1[CH2:20][C@@H:16]([NH:15][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[O:14])[CH2:17][C@H:18]1[CH2:28][C:29]([OH:31])=[O:30])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a stirred solution of tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (0.65 g, 1.46 mmol, step 5 of Example 9) in methanol (10 mL) was added 2N sodium hydroxide aqueous solution (10 mL) at room temperature and the mixture was stirred for 2.5 h. The resulting solution was acidified with 2N hydrochloric acid to be pH 3. Then the mixture was extracted with dichloromethane (10 mL×3). The organic layer was dried over sodium sulfate and concentrated to give 0.62 g (98%) of the title compound as a colorless oil. The residue was used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[SH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:17]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Ethyl bromoacetate (21.5 mL, 194 mmol) and potassium carbonate (50.7 g, 367 mmol) were added to a DMF (450 mL) solution of 4-mercaptophenol (23.1 g, 183 mmol), and the mixture was stirred at room temperature overnight. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 30.3 g (78%) of the captioned compound.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:6][CH2:7][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CCCC(=O)OCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl butyrate (49 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester.