Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24]([NH2:26])=[O:25])=[N:10]2)[CH2:5][CH2:4]1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:27]([O:31][C:32](=[O:33])[NH:34][CH2:35][C:36]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24](=[O:25])[NH2:26])=[N:10]2)[CH2:5][CH2:4]1)=[O:37])([CH3:30])([CH3:28])[CH3:29]
Reactant: CSc1ncc2ccc3c(C(N)=O)nn(C4CCC(N)CC4)c3c2n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ncc2ccc3c(C(N)=O)nn(C4CCC(NC(=O)CNC(=O)OC(C)(C)C)CC4)c3c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
30 mg (0.084 mmol) of 1-(4-aminocyclohexyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride were dissolved in 2 ml of dimethyl acetamide. To the obtained solution 21 mg (0.126 mmol) of N-(tert-butoxycarbonyl)glycine, 60 μl (0.336 mmol) of DIPEA, 40 mg (0.126 mmol) of TBTU were added. The mixture was stirred at room temperature for 18 hours, the solution was portioned between ethyl acetate and saturated aqueous solution of NaHCO3, the organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude was purified by silica gel chromatography (DCM/MeOH/NH4OH 95/5/0.1) to provide tert-butyl[2-({4-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]cyclohexyl}amino)-2-oxoethyl]carbamate 35 mg (81%) as a white solid. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.27 (d, J=8.67 Hz, 1H), 7.78 (d, J=6.35 Hz, 1H), 7.74 (d, J=8.67 Hz, 1H), 7.64 (br. s., 1H), 7.55 (br. s., 1H), 6.86 (t, J=5.86 Hz, 1H), 6.00 (br. s., 1H), 3.96 (d, J=2.56 Hz, 1H), 3.62 (d, J=5.61 Hz, 2H), 2.72 (s, 3H), 2.23-2.36 (m, 2H), 1.91-2.11 (m, 4H), 1.68-1.82 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:21][CH:20]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 42.9 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-yl-1,4-diazepan-1-yl)benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-isopropyl-1,4-diazepan-1-yl)benzoate (0.212 g, 0.73 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.181 g, 0.73 mmol) and a 2M solution of trimethylaluminium (0.913 ml, 1.83 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum which solidified on trituration with DCM/Ether to afford the title compound (0.154 g, 42.9%) as a cream solid.
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1([CH3:15])[C:10](=[O:11])[CH2:9][C:8]([CH2:13][CH3:14])([CH3:12])[O:7]1)[CH3:5].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([CH2:25][CH3:26])[CH:18]=1.Cl>C(COC)OC>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:9]2[C:8]([CH2:13][CH3:14])([CH3:12])[O:7][C:6]([CH2:4][CH3:5])([CH3:15])[C:10]2=[O:11])=[C:19]([CH2:25][CH3:26])[CH:18]=1
Reactant: CCC1(C)CC(=O)C(C)(CC)O1
Reactant: CCc1cc(Br)ccc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(Br)ccc1C=C1C(=O)C(C)(CC)OC1(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.8 %

Procedure:
Sodium methoxide (5.08 g, 0.094 mol) is added to a solution of 2,5-diethyl-2,5-dimethyldihydrofuran-3-one (8 g, 0.047 mol) in dimethoxyethane (40 ml) at 0° C. The reaction mixture is stirred for 15 minutes at 0° C. and a solution of 4-bromo-2-ethyl benzaldehyde (8.96 g, 0.042 mol) in dimethoxyethane (8 ml) is added. The reaction mixture is stirred at 0° C. for 1 hour, acidified to pH 1 with 2N aqueous hydrochloric acid and extracted with diethyl ether (3×75 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure to give 4-[1-(4-bromo-2-ethylphenyl)methylidene]-2,5-diethyl-2,5-dimethyldihydrofuran-3-one (17 g), used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[CH:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cncc(Br)c1
Product: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-(trifluoromethyl)-phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([NH:23][C:24](=[O:29])C(F)(F)F)[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16]4([O:17][CH2:18][CH2:19][O:20]4)[CH2:21][CH2:22]3)[NH:23][C:24]2=[O:29])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(Cl)cc1)N1CCC2(CCC3(CC2)OCCO3)NC1=O

Procedure:
The title compound is prepared from N-(8-{2-[(S)-1-(4-chloro-phenyl)-ethylamino]-ethyl}-1,4-dioxa-spiro[4.5]dec-8-yl)-2,2,2-trifluoro-acetamide and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2. Yield: quantitative (crude); Mass spectrum (ESI+): m/z=365/367 (Cl) [M+H]+.
Reaction SMILES: [OH-].[NH4+:2].[SH2]=N.[C:5]1([NH:11][C:12](C2C=CC=CC=2C(O)=O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O>[C:5]1([NH:11][C:12]([NH2:2])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: [NH4+]
Agent: N=[SH2]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)Nc1ccccc1

Procedure:
1 ml of an aqueous ammonium hydroxide solution (25%) was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml acetone, under stirring. The reaction mixture was stirred for 30 minutes at ambient temperature, then evaporated in vacuo and the residue was crystallized from water. 0.60 g phenylurea melting at 148°-150° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=O)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)[CH3:2].O.[NH2:16][NH2:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[NH:17][N:16]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C(=O)C1CCCCC1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1n[nH]c2c1CCCC2

Procedure:
A solution of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester [7.5 g, Reference Example 19(a)] in acetic acid (150 ml) was treated dropwise with hydrazine monohydrate (1.65 ml). The mixture was refluxed for 8 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) and the organic layer was dried over sodium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (606 mg) as an orange oil which solidified on standing. LC-MS (METHOD B): RT=2.79 minutes; 195 (M+H)+. (b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[P:30](=[O:34])([OH:33])([OH:32])[OH:31]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[P:30]([O-:34])([O-:33])([O-:32])=[O:31]
Reactant: O=P(O)(O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=P([O-])([O-])[O-]
Temperature: 30 °C

Procedure:
Sunitinib (1.0 g) was suspended in methanol (152 mL), followed by addition of phosphoric acid (0.29 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib phosphate. (1.11 g; yield: 88%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](/[CH:12]=[CH:13]/[C:14]([N:16]2[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][O:18][C:17]2=[O:28])=[O:15])=[CH:4][C:3]=1[Cl:29]>[Ni].CO>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([N:16]2[C@H:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][O:18][C:17]2=[O:28])=[O:15])=[CH:4][C:3]=1[Cl:29]
Reactant: Nc1c(Cl)cc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: Nc1c(Cl)cc(CCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 23.7 g (55.8 mmol) of (R)-3-[(E)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acryloyl]-4-benzyl-oxazolidin-2-one, 400 mL of MeOH and 5.0 g of Raney nickel was shaken for 2 h at RT and 3 bar of H2 in a Parr autoclave. The catalyst was suction filtered and the solvent removed i. vac. The desired product was obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[N:9][N:8]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[C:5]2=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C2CCCCO2)c2ncc(Br)cc12
Yield: 93.2 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IX) (0.250 g, 0.88 mmol) in dry DCM (10 mL) was added 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) and refluxed 5 h under nitrogen. Another equivalent of 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) was added and the solution was further heated at refluxed overnight under nitrogen. The solution was cooled, diluted with DCM, washed subsequently with a saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (X) as a viscous liquid (302 mg, 0.82 mmol, 93% yield). 1H NMR (CDCl3) δ ppm 1.51-1.62 (m, 2 H), 1.91-2.13 (m, 2H), 2.33-2.44 (m, 2H), 3.40 (s, 3 H), 3.66 (m, 1H), 3.75 (s, 3H), 3.87-3.98 (m, 1 H), 6.07 (dd, J=10.07, 2.52 Hz, 1 H), 8.57 (d, J=3.01 Hz, 1 H), 8.73 (d, J=3.01 Hz, 1 H); ESIMS found for C14H17BrN4O3 m/z 369.4 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17][C:16](=S)[NH:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:44][NH2:45].[O-]S([O-])=O.[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:17]/[C:16](=[N:45]\[CH3:44])/[NH:15]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH3:2]
Reactant: CN
Reactant: CCOc1cc(C2NC(=S)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Solvent: CCO
Product: CCOc1cc(C2N/C(=N/C)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
A mixture of crude 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione (Compound 8) (392 mg, 0.877 mmol), m-CPBA (887 mg of 85% purity, 4.38 mmol) and aqueous methylamine solution (3 mL) in ethanol (20 mL) was stirred at 0° C. for 2 h, then at room temperature overnight. Na2SO3 (2 g) was added and then dilute hydrochloride acid was added drop wise to adjust the pH to about 6. The above mixture was extracted with ethyl acetate (40 mL×3), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography, followed by preparative HPLC twice to afford Compound 117 (26 mg, yield: 6.7%). 1H NMR (DMSO-d6 400 MHz): δ 8.73 (s, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.53 (s, 1H), 7.48 (s, 2H), 7.33 (s, 4H), 7.10-7.11 (m, 3H), 7.01 (s, 1H), 6.89-6.91 (m, 3H), 5.22 (s, 1H), 3.93 (d, J=6.8 Hz, 1H), 2.78 (s, 3H), 1.24-1.27 (t, J=4.8 Hz, 3H); MS (ESI): m/z 445.2[M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[Cl:13]
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: Oc1ccc(F)cc1Cl
Product: Fc1ccc(Oc2ccnc3c(Cl)cccc23)c(Cl)c1
Temperature: 160 °C
Yield: 49.5 %

Procedure:
A mixture of 2.0 g of 4,8-dichloroquinoline and 2.96 g of 2-chloro-4-fluorophenol was heated to 160° C. and stirred. Progress of the reaction was monitored using TLC. When no 4,8-dichloroquinoline remained, the product was washed with base to remove phenol, then purified using HPLC. A brown solid resulted, which was recrystallized in heptane to give 1.54 g of the title product as yellow crystals. Yield: 49%. M.P. 99°-101° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](OCCCCCCBr)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 15.0 g (60 mmol) trans-4-Hydroxy-cyclohexylcarbamic acid benzyl ester suspended in 183 ml (1.2 mol, 20 eq) 1,6-Dibromohexane, 6.1 g (i8 mmol, 0.3 eq) tetrabutyl-ammoniumhydrogensulfate and 183 ml 50% aqueous NaOH were added. The mixture was stirred at RT for 4 days, CH2Cl2 was added and the layers were separated. The inorganic layer was extracted with CH2Cl2, the combined organic layers were washed with brine and dried over Na2SO4. The excess of dibromide was removed in vacuo and the residue was purified by column chromatography on silica gel with hexane:EtOAc 1:1 as eluent yielding 3.4 g (14%) trans-[4-(6-Bromo-hexyloxy)-cyclohexyl]-carbamic acid benzyl ester as white solid, MS: 412 (MH+, 1Br) and 11.2 g (32%) trans-(6-Bromo-hexyl)-[4-(6-bromo-hexyloxy)-cyclohexyl]-carbamic acid benzyl ester as yellow oil, MS: 574 (MH+, 2Br).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](C)=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].C1(CN2[C:32](=[O:33])C(OC)C(=C=O)C(C3C=CC(OC)=C(F)C=3)=N2)CC1>>[C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:33][CH3:32])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Reactant: COc1ccc(C2=NN(CC3CC3)C(=O)C(OC)C2=C=O)cc1F
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1 (7), 2-cyclo-propylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxy-carbonyl-2H-pyridazin-3-one was reacted to yield the title compound as yellow crystals (yield: 98.9%).
Reaction SMILES: [CH2:1]([C:4]([OH:25])([CH2:22][CH:23]=[CH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[CH:2]=[CH2:3].Cl.[CH3:27]COCC>>[CH2:1]([C:4]([OH:25])([CH2:22][CH:23]=[CH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([O:19][CH3:27])=[O:18])[CH:2]=[CH2:3]
Reactant: CCOCC
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Agent: Cl
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)OC
Reaction time: 2 h

Procedure:
A cooled ether solution of 2.4 g of the product of Example 8 was added to excess CH2N2 in ether at 0° to 5°; after standing 2 hours, the excess CH2N2 was decomposed with dilute HCl. The ether layer was washed with H2O, with dilute NaHCO3, dried (K2CO3) and evaporated. The residue, 2.5 g, was flash chromatographed on a 10×20 cm column of silica gel in 20% C2H5OCOCH3 --CH2Cl2 ; a single fraction of 0.37 g was used for; a total of 1.35 g of title compound was obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:20][C:21]1[CH:22]=[N:23][C:24]([C@@H:27]([NH2:29])[CH3:28])=[N:25][CH:26]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5]([NH:29][C@H:27]([C:24]2[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=2)[CH3:28])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 60 %

Procedure:
A mixture of 5-bromo-2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 13, 150 mg, 0.45 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 88 mg, 0.5 mmol) and DIPEA (0.12 ml) in n-BuOH (2 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (20-60% EtOAc in hexanes) to give the titled compound as solid (118 mg, 60%). NMR: 11.98 (s, 1H), 9.36 (s, 1H), 8.82 (s, 2H), 8.10 (s, 1H), 7.96 (s, 1H), 5.56 (s, 1H), 5.13 (s, 1H), 4.66 (m, 1H), 1.48 (m, 3H), 1.26 (m, 6H); m/z 437.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=2[O:18]1.C(O)(=O)C1C=CC2OCOC=2C=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:17]1[O:28][C:27]2[CH:26]=[CH:25][C:21]([C:22]([NH:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:16][CH:15]=3)=[O:23])=[CH:20][C:19]=2[O:18]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCc1ccc(OCCN2CCCC2)cc1
Agent: O=C(O)c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccc(OCCN2CCCC2)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a cooled solution of 20.0 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 30 ml of chloroform was added 17.7 g of 3,4-methylenedioxybenzoyl chloride (which was prepared with 15.9 g of piperonylic acid and 65.3 g of thionyl chloride in the usual manner). The mixture was stirred at room temperature for 20 minutes and the solvent was evaporated. 150 ml of water was added to the residue and the mixture was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was washed with isopropyl ether to give 30.0 g of colorless crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 93.5°-94.5° C.
Reaction SMILES: [O-2:1].[Mg+2:2].[O-2].[Ca+2:4].[Mg].[O-2].[Ca+2].[C:8](=[O:10])=[O:9]>O>[C:8](=[O:1])([OH:10])[O-:9].[Mg+2:2].[C:8](=[O:1])([OH:10])[O-:9].[C:8](=[O:1])([OH:10])[O-:9].[Ca+2:4].[C:8](=[O:1])([OH:10])[O-:9]
Reactant: [O-2]
Reactant: O=C=O
Agent: [Ca+2]
Agent: [Mg+2]
Agent: [Mg]
Solvent: O
Product: O=C([O-])O
Reaction time: 5 h

Procedure:
A mixture of magnesium oxide and calcium oxide, prepared from calcination of dolomite at 900° C. for 2 hours, is hydrated for 5 hours at 50° C. The weight ratio of water to magnesium/calcium oxide is 5:1. Then water is added into the mixture to prepare slurry at a weight ratio of water to magnesium/calcium oxide of 190:1. After that, carbon dioxide (75 vt %) is introduced into the slurry to react for 2 hours at 25° C. Subsequently, a pure aqueous solution of magnesium bicarbonate and calcium bicarbonate (MgO+CaO (90 wt % MgO): 5.1 g/L, Fe: 1.1 ppm, Al: 0.7 ppm) is obtained after clarification and filtration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:9])#[N:2].[OH-:27].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:9])(=[O:27])[NH2:2]
Reactant: [OH-]
Reactant: C[C@H](CO)Nc1ccc(C#N)cc1C(=O)NCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)Nc1ccc(C(N)=O)cc1C(=O)NCc1ccc2c(c1)OCO2

Procedure:
To a solution of (R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (76 mg) in ethanol (6 mL) was added 1N-sodium hydroxide (0.65 mL), and the mixture was heated for 6 hours under reflux. The solvent was evaporated in vacuo. The residue was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (9:1) to give (R)-5-carbamoyl-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (27 mg) as a solid substance.