Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:24])[CH:21](O)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(O)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:36][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:24])([CH3:34])[CH3:35])=[CH:30][CH:31]=1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)C(O)O)N1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
300 mg (0.91 mmol) of 6-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg (1.09 mmol) of 2-(4-fluorophenyl)-1,1-dimethylethylamine were dissolved in 3 mL of ethanol. Molecular sieve was added and the mixture was heated to 80° C. for 30 minutes. After cooling to ambient temperature, 35 mg (0.91 mmol) of sodium borohydride was added. The mixture was stirred for 1 hour at ambient temperature, then sodium hydrogen carbonate solution was added to the reaction mixture and it was extracted with ethyl acetate. The organic phases were evaporated down and the residue was chromatographed (eluent: hexane-ethyl acetate-methanol). The ethanolamine thus obtained (223 mg) was dissolved in methanol to cleave the benzyl protecting group and hydrogenated with 150 mg palladium hydroxide as catalyst at ambient temperature and normal pressure. The catalyst was separated off by filtering through CELITE® filter agent, the filtrate was freed from solvent and the residue was chromatographed (silica gel; eluent: dichloromethane-methanol). Beige solid. Yield: 76 mg (22%); mass spectrometry: [M+H]+=375.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.O=S(Cl)Cl.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)nc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)cn1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 5-aminopicolinic acid (110; 8.4 g, 60.8 mmol) in ethanol (100 mL) was added SOCl2 (14.5 g, 120 mmol) at 0° C. The mixture was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Enough saturated aqueous Na2CO3 solution was added to adjust pH=9. The resulting mixture was filtered and the solids were dried under reduced pressure to afford ethyl 5-aminopicolinate 111 (7.5 g, 75%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([CH2:33]O)=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]=[N:29]1.C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:33][C:32]1[N:28]([C:22]2[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:27])[N:29]=[N:30][C:31]=1[C:35]([F:38])([F:37])[F:36]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1nnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
Triphenylphosphine (16.4 g, 62.5 mmol) is added to a suspension of [3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]-methanol (13 g, 41.69 mmol) in dichlormethane (80 mL). The mixture is cooled to 0° C. and carbon tetrabromide (20.7 g, 62.5 mmol) is added. The reaction is stirred at room temperature for 1.5 hours. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography eluting with hexanes/EtOAc (95:5 to 8:2) to obtain the title compound (15.6 g, 96% yield). ES/MS m/e 374 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(380 mg, 1.0 mmol) was dissolved in 3-amino-1-propanol(5 ml), then reacted at the same condition of Step 5 in the Example 1 to obtain 313 mg of desired compound as solid in 75% of yield.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH2:34]>CO>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (400 mg, 0.78 mmol) in methanol (10 mL) was added methyl vinyl sulfone (207 mg, 1.95 mmol). The resultant reaction stirred at ambient temperature for 24 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (446 mg, 92%). 1H NMR (300 MHz, DMSO-d6): 9.46 (d, J=0.4 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.24-8.24 (m, 2H), 7.78 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 4.86-4.86 (m, 1H), 3.27 (t, J=7.1 Hz, 2H obscured solvent peak), 3.03 (s, 3H), 2.92-2.80 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.21 (t, J=10.9 Hz, 2H), 2.22-1.98 (m, 2H), 1.92-1.92 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].I[CH3:26].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:26])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CI
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 5.98 g) was added in portions to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 30, 10 g, 30 mmol) in dimethylformamide (100 mL) and the mixture was stirred at 0° C. for 30 min. Iodomethane (9 mL) was added in one portion and the mixture was stirred at room temperature for 30 min. Water (1.5 L) was added and the mixture was extracted with ether (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (240 mL) and aqueous sodium hydroxide (4M, 60 mL) was added. The mixture was heated under reflux for 1 h., cooled and the pH was adjusted to 1.0 with hydrochloric acid (2M). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the title compound (7.5 g, 72%). 1H NMR (360 MHz, CDCl3) δ 7.58 (1H, d, J 1.8 Hz), 7.44-7.48 (2H, m), 7.18-7.30 (4H, m), 3.53 (3H, s), 2.96-3.00 (2H, m), and 2.54-2.59 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH:13]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5](/[CH:13]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=[N:3]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1ncc(C=O)c1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnn(C)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carbaldehyde (750 mg), sodium hydride (60% in oil, 176 mg), ethyl diethylphosphonoacetate (1.08 g) and N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazol-4-yl]acrylate (770 mg, 75%) as pale-yellow prism crystals. melting point: 159-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([F:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2sc(F)cc21
Product: CC1c2cc(F)sc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-fluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C(N(CC)CC)C.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27]>C(Cl)Cl>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:7]2[CH2:6][CH2:5][N:4]([S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])[C:3]3([CH2:1][CH2:2]3)[CH2:8]2)=[N:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
N-(oxomethylene)sulfamoyl chloride (13.4 mmol) was dissolved in dry benzene (5 mL) and dropwise added t-BuOH (13.4 mmol) while the temperature was kept below 25° C. The reaction mixture was stirred at 25° C. for 2 h, added hexane (5 mL) and cooled to 0° C. Precipitate was collected by filtration, washed with hexane affording tert-butyl N-chlorosulfonylcarbamate as white crystals. 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.6 mmol) (intermediate 21) was suspended in dry DCM (25 mL) and added triethylamine (6.9 mmol). To this suspension was slowly added tert-butyl N-chlorosulfonylcarbamate (4.6 mmol) at rt. After 15 min all starting material has been consumed. The obtained reaction mixture was concentrated in vacuo on celite. The product was purified by flash chromatography on silica using EtOAc:MeOH in heptane as eluent.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[CH2:12]([S:28]([O-:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+]>C(O)C>[CH2:12]([S:28]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11])(=[O:30])=[O:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCS(=O)[O-]
Reactant: O=C1Cc2ccccc2C1Br
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCS(=O)(=O)C1C(=O)Cc2ccccc21
Reaction time: 0.5 h

Procedure:
16.6 g of 1-bromo-2-indanone are added with stirring to a hot solution of 26.0 g of potassium hexadecylsulphinate in 100 ml of ethanol. The mixture is stirred for a further 30 minutes without further heating and then precipitated with 100 ml of water. The resulting precipitate is recrystallised from 200 ml of methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:40].[Na+]>CC(CC)=O>[N+:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][I:40])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Temperature: 25 °C

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine (35.82 g) was dissolved in 90 ml of methylethylketone, and 19.29 g of sodium iodide was added thereto, followed by stirring under reflux for 1 hour. The reaction mixture was cooled down to room temperature and filtered. The filtrate was distilled to remove the solvent. The residue was diluted with ethyl acetate, washed successively with water, a sodium hypochlorite solution and water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-iodomethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:40]=[CH:39][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH2:35][CH:36]4[CH2:38][O:37]4)=[C:29]([C:32]#[N:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:19][C:18]=1[F:41]>O>[C:32]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH2:35][CH:36]1[CH2:38][O:37]1)[N:25]=[CH:24][CH:23]=[C:22]2[O:21][C:20]1[CH:39]=[CH:40][C:17]([NH:16][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[O:15])=[C:18]([F:41])[CH:19]=1)#[N:33]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding dimethylformamide (2 ml) and 4-fluorophenyl isocyanate (0.15 ml) to 4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxy-quinoline-6-carbonitrile (400 mg), the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the precipitated crystals were filtered off to obtain the title compound (480 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(C)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.37 g, 0.007 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (4.30 g, 0.033 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (2.00 g, 0.007 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 15%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)cn1-c1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: O
Product: CCc1nc(C)cn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, reaction of 4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([CH3:38])=[C:8]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:31]=2)[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([CH3:24])=[N:15]2)[CH3:13])[CH:11]=1.C(N(C(C)C)CC)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:35]1[CH2:34][CH2:33][CH:32]([N:30]2[CH:31]=[C:27]([C:8]3[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]4[C:18]5=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]5[C:16]([CH3:24])=[N:15]4)[CH3:13])[CH:11]=[C:6]([Cl:5])[C:7]=3[CH3:38])[CH:28]=[N:29]2)[CH2:37][CH2:36]1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCN(C(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
Acetyl chloride (2.4 μL, 0.033 mmol) was added to a solution of 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.0 mg, 0.017 mmol, chiral intermediate from Example 181, Step 2) and N,N-diisopropylethylamine diisopropylethylamine (14 μL, 0.083 mmol) in methylene chloride (0.3 mL) at 0° C. and the reaction was stirred at room temperature for 15 min. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.0 mg, 7.8%). The product was isolated as a single enantiomer. LCMS calculated for C26H32ClN8O2 (M+H)+: m/z=523.2; Found: 523.2.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([C:10]3([NH:23]S(C(C)(C)C)=O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]1)[CH2:14]2)(C)(C)C.Cl>CC(O)C>[C:17]1([C:10]2([NH2:23])[CH:11]3[CH2:16][C:7]4([OH:6])[CH2:14][CH:13]([CH2:15][CH:9]2[CH2:8]4)[CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)NC1(c2ccccc2)C2CC3CC1CC(O[Si](C)(C)C(C)(C)C)(C3)C2
Agent: Cl
Solvent: CC(C)O
Product: NC1(c2ccccc2)C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [5-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-adamantan-2-yl]-amide (6) in 2-propanol (10 mL) was added 1N hydrochloric acid (5 mL) and the mixture was stirred at room temperature until complete conversion was achieved. The reaction mixture was washed with diethyl ether, the aqueous phase was concentrated in vacuo and lyophilized to yield 676 mg of a diastereomeric mixture of 4-phenyl-4-amino-adamantan-1-ol (7) as its hydrochloride. Rt=0.33 min, 0.85 min (Method 3). Detected mass: 227.2 (M-NH3+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH3:27][C:20]([C:28]1[CH:29]=[C:30]([S:34]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)c1

Procedure:
(S)-Arginine (12.6 g) and K2CO3 (12.03 g) are suspended in 50% water/dioxan (250 ml) with vigorous stirring and the reaction mixture is cooled to <5° C. 3-(α,α-Dimethylbenzyl)benzenesulphonyl chloride (21.4g) is added in 6 portions over 30 minutes at <5° C. The mixture is stirred at 20° C. for 2 hours. A colourless solid precipitates. The dioxan is removed by evaporation and the aqueous residue is acidified with cone. HCl. The mixture is extracted with ethyl acetate (3×50ml) and the aqueous phase and all solid materials are combined and neutralised (4M NaOH). The suspension is stirred for 16 hours at 20° C. The solid precipitate is collected by filtration and stirred for 16 hours with a little water. The solid is collected by filtration and dried (NaOH pellets) to give Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-arginine, m.p. 122°-124° C. (Found: C, 53.49; H, 6.81; N, 11.92; S, 6.93. C21H28N4O4S.2.3H2O requires C, 53.22; H, 6.93; N, 11.82; S, 6.77%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N:15]([CH:26]([CH3:32])CC(OC)=O)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C1C[O:36][CH2:35]C1>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([N:15]([C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[Cl:7])[C@H:26]([CH3:32])[CH2:35][OH:36])(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: COC(=O)CC(C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@H](CO)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of LAH (18.5 mL of a 1M solution in THF, 18.5 mmol) in THF (50 mL) at −78° C. was added dropwise a solution of N-(2,5-dichlorophenyl)-N-(1-carbomethoxyprop-2-yl)-4-chlorobenzenesulfonamide (6.5 g, 15.4 mmol) in THF (100 mL). After the addition was complete, the reaction was briefly allowed to warm to 0° C. followed by cooling to −78° C. The suspension was quenched with 0.5N HCl (20 mL) and stirred at room temperature for 3 h. The resulting precipitate was removed by filteration and the filter cake washed well with Et2O. The filtrate was dried over MgSO4 and concentrated in vacuo to afford 4-chloro-N-(2,5-dichlorophenyl)-N-(1R)-(2-hydroxy-1-methylethyl)benzenesulfonamide as a white wax (5.88 g, 98% yield): 1H NMR (CDCl3) δ 7.77 (d, 2H, J=7.0 Hz), 7.34–7.52 (m, 5H), 4.27–4.42 (m, 1H), 3.35–3.61 (m, 2H), 1.77 (s, br, 1H), 1.05–1.09 (m, 3H).