Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a suspension of 3-(3-trifluoromethoxy-phenyl)-acrylic acid (2.21 g, 9.53 mmol) in THF (15 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (2.42 g, 19.06 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.99 g (45%) 3-(3-trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>O1CCCC1.CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[CH:4][C:3]=1[NH2:19]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2Cl)cc1OC(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2cc(N)c(Cl)cc2Cl)cc1OC(F)F

Procedure:
1.5 g (4.2 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)nitrobenzene were dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol and admixed with 4 g of Raney nickel. The mixture was stirred at room temperature under a gage pressure of 0.3 bar of hydrogen for 4 h and then filtered through kieselguhr. The filtrate was dried using magnesium sulfate and then evaporated to dryness. This gave 1.3 g of the aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH2:18]([SH:20])[CH3:19].[Na]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[S:20][CH2:18][CH3:19]
Reactant: CCS
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]

Procedure:
A solution of 7-Chloro-1,4-dihydro-6-fluoro-5-nitroquinoxaline-2,3-dione (0.100 g, 0.385 mmol) and ethanethiol, sodium salt (0.130 g, 1.55 mmol) in DMSO (1.0 mL) was stirred at room temperature for 24 h. The resulting solution was diluted with water (5 mL) and acidified with concd HCl (4-5 drops) to pH ~5. The precipitated solid was collected by filtration under vacuum, washed with water (10 mL), and dried under vacuum to obtain 0.098 g (84%) pure (HPLC) title compound as a yellow powder; mp darkens at 323° C.; 1H NMR (DMSO-d6) δ1.04 (t, 3H, J=7.2 Hz), 2.82 (q, 2H, J=7.5 Hz), 7.34 (s, 1H), 12.20 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [OH:1][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:3].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[CH2:40]([O:3][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:1])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 250-mL round-bottom flask were added 2-methyl-acrylic acid 6-[4-(2-hydroxycarbonyl-vinyl)-phenoxy]-hexyl ester (4.98 g, 15.0 mmol), 1-hexadecanol (4.00 g, 16.5 mmol) and DMAP (92 mg, 0.75 mmol) as solids and a stirbar. The flask was purged with N2, followed by the addition of CH2Cl2 (35 mL). The suspension was stirred at room temperature for 20 min to give a white slurry. The flask was cooled in an ice bath and DCC (3.25 g, 15.75 mmol) was introduced. The mixture quickly became a light yellow solution, which was then removed from the ice bath and stirred at room temperature. After 20 h, the resulting white slurry was loaded on a SiO2 column (˜100 g) for quick purification. The product was eluted off with 10% EtOAc in hexanes. The fractions with the desired product were combined, concentrated and then dried in vacuo to a white solid (7.17 g, 86%) of Addition Monomer 7.
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Temperature: 85 °C
Reaction time: 9 h

Procedure:
3-(R,S)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine (30 g--see Preparation 7) was dissolved in 95% sulphuric acid (210 ml) and the mixture was heated, with stirring, at 85° C. for 9 hours and then at 100° C. for 30 minutes. The mixture was allowed to cool to room temperature and poured onto ice (2 kg). The mixture was basified (pH 12) by addition, in portions with cooling in an ice bath, of a cold solution of sodium hydroxide (340 g) in water (500 ml). The resulting mixture was extracted with dichloromethane (3×300 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a foam, yield 16.4 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[NH2:9][CH2:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]([CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH:17]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH2:27][N:16]([CH2:15][C:14]1[CH:37]=[CH:38][C:11]([CH2:10][NH:9][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:12][CH:13]=1)[CH:17]1[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1
Reactant: Cn1ccnc1C=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 67.5 %

Procedure:
Using General Procedure B: A solution of 1-methyl-2-imidazole carboxaldehyde (27.5 mg, 0.25 mmol) and (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (100 mg, 0.25 mmol) in MeOH (2.0 mL) was stirred overnight at room temperature. NaBH4 (37.5, 0.75 mmol) was added and the resultant mixture stirred for an additional 15 minutes. Purification of the crude white foam by column chromatography on silica gel (CH2Cl2[MeOH/NH4OH, 50:1:1) followed by radial chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 200:3:2) afforded the desired amine (83 mg, 67%) as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 1-(4-nitrophenyl)cyclopropanecarboxylic acid (500 mg) obtained in Step B of Example 145 in ethanol (10 mL) was added palladium-activated carbon ethylene diamine complex (Pd 8.5 to 11.5%) (100 mg), and the mixture was stirred overnight at room temperature under hydrogen atmosphere (at normal pressures). The palladium carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (260 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.O.C(O)(=O)C.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=O)#[N:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:27]([C:26]3[CH:25]=[C:24]([CH:32]=[CH:31][CH:30]=3)[C:22]#[N:23])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2nnc3ccc(Cl)nn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (6-chloropyridazin-3-yl)hydrazine and triethylamine in THF, 3-cyanobenzoyl chloride was added with cooling in ice, and stirred at room temperature for 1 hour. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and diethyl ether to obtain, N′-(6-chloropyridazin-3-yl) -3-cytanobenzohydrazide. To this, acetic acid was added, and the mixture was stirred at 110° C. for 2 hours, the reaction solution was concentrated under reduced pressure, and the resultant crude crystal was washed with ethanol to obtain 3-(6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)benzonitrile. Dat (F:256).
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10]>>[OH:5][CH2:4][C@H:3]([CH3:6])[CH2:2][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:24])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CO)CCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)CO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (2S)-3-chloro-2-methyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:8][CH2:7]1.[ClH:38].C(OCC)(=O)C>>[ClH:38].[F:37][C:2]([F:1])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A reaction mixture of tert-butyl N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycinate (13.3 g) and 4N hydrogen chloride/ethyl acetate (80 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated to give the title compound (12.8 g).
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)/[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)/[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[S:19])=[C:6]([C:9]4[S:10][C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 71.3 %

Procedure:
350 mg of diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as synthesized in the same manner as in Example 1 (b) above were dissolved in ml of methylene chloride, and to the solution obtained were added 531 mg of (Z)-2-(2-tritylaminothiazol-4-yl)-trityloxyiminoacetic acid, 0.21 ml of pyridine and 74 μl of phosphorus oxychloride. Next, the acylation reaction and the post-treatment of the reaction solution were carried out in the same way as in Example 1 (b), and the resultant residue was then purified by a column chromatography on 35 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate, 10:1) to obtain 566 mg of the titled compound (yield, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][S:59][CH2:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:62][C@H:57]([C:55]1[NH:54][C:53]2[CH:63]=[CH:64][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][S:59][CH2:60][CH3:61])=[O:7]
Reactant: CCSC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CCSC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 75 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-ethylsulfanylethylamine in tetrahydrofuran. Yield: 75%; Rf value: 0.41 (silica gel; dichloromethane/ethanol=9:1); C23H24Cl2N4O2S (491.44); mass spectrum: (M+H)+=491/493/495 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc2c(-c3cn[nH]c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give (1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-amine. LC-MS m/e 277(MH+).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29]1(C2C=CC=CC=2)C=CC(C[C@@H](NC(OC(C)(C)C)=O)C[C@H](C)C(O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CI.C(OC(C)C)(=O)C>O.CN(C)C=O>[CH3:29][O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H), ratio of diastereomers of 80:20 ratio, respectively, prepared according to Example 3 in WO/2008/031567, is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Methyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me) as an 80:20 mixture of diastereomers, respectively. 1H NMR (CDCl3): 1.17-1.20, 1.25-1.26, 1.41, 1.46-1.63, 1.76-1.85, 1.92-1.99, 2.51-2.59, 2.61-2.71, 2.76-2.85, 3.70, 3.83-3.99, 4.09-4.40, 7.25-7.28, 7.33-7.37, 7.43-7.47, 7.53-7.55, 7.59-7.61. Ratio of diastereomers 80:20 (1-a, R1=Boc, R2=H, R3=CO2Me: 1-b, R1=Boc, R2=H, R3=CO2Me) by integration of signals at 1.76-1.85 (1-b, R1=Boc, R2=H, R3=CO2Me) and 1.92-1.99 (1-a, R1=Boc, R2=H, R3=CO2Me).
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.[F:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][C:41]=1[NH2:42].C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=1>ClCCCl.CN(C)C=O>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:42][C:41]3[CH:40]=[CH:39][N:38]=[CH:37][C:36]=3[F:35])=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1ccncc1F
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A ˜1:1 mixture 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid 1D (4.7 g, 18.6 mmol) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (2.65 mL 30.4 mmol) followed by N,N-dimethylformamide (0.08 mL, 1.034 mmol). The reaction mixture was heated at 65° C. for 5 hours, concentrated and dried under high vacuum for 1 hr and taken into the next step without further purification. The crude mixture of acid chloride was suspended in DCE (100 mL) and treated with 3-fluoropyridin-4-amine (2.73 g, 24.31 mmol) and N,N-diisopropylethylamine (5.31 mL, 30.4 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered through Buchner funnel, washed with DCE (2×25 mL) to isolate a 1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (5.2 g, 15.0 mmol, 80% yield) as light brown solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.1 (M+H=326.07 and M+H=372.01).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:19]3[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]4)=[N:17][CH:16]=[N:15][C:14]=3[S:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][NH:37][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:18]2[C:19]3[C:11]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:12][S:13][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: CN1CCCC1CCN
Reactant: O=C(O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCCC1CCNC(=O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (26 μL, 0.35 mmol) was added to (1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 0.294 mmol) in dry DCM at 0° C. The reaction was stirred for 30 min then 2-(1-methylpyrrolidin-2-yl)ethanamine (173 μL, 0.294 mmol) and triethylamine (82 μL, 0.588 mmol) were added and the reaction stirred for a further 10 min at 0° C. and then stirred at room temperature for 1 hr. The reaction was reduced to dryness in vacuo and the residue purified by prep HPLC (Basic, method F) to give the desired compound as an off-white solid. Yield=70 mg. LCMS [M+H]+=450; RT=3.01 min
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH:2]([CH3:10])[CH3:1])[S:6][CH:7]=1
Reactant: BrBr
Reactant: CC(C)C(=O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)c1cc(Br)cs1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
2-methyl-1-(2-thienyl)-1-propanone (2.3 g, 15 mmol) was diluted in chloroform (10 mL), and aluminum chloride (4.5 g, 34 mmol, 2.3 eq) was added. Bromine (0.82 mL, 16 mmol, 1.1 eq) was added as a solution in chloroform (15 mL), and the mixture was stirred at rt over the weekend. The crude reaction mixture was carefully poured onto ice water, then extracted with chloroform. The combined organics were dried over sodium sulfate, filtered, and concentrated to afford brown oil. The crude was purified by isco combiflash to give the title compound as brown oil (1.28 g, 40%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([CH3:27])[C:24]([CH3:26])=[CH:25][C:19]=4[N:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:26][C:24]1[C:23]([CH3:27])=[CH:22][C:20]2[NH:21][C:17]([C:16]3[C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[NH:14][N:15]=3)=[N:18][C:19]=2[CH:25]=1
Reactant: Cc1cc2nc(-c3n[nH]c4c3CN(C(=O)OC(C)(C)C)CC4)[nH]c2cc1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Reaction time: 16 h
Yield: 70.9 %

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester [1.014 g, Example 252(a)] in methanol (20 ml) was treated with a solution of hydrogen chloride in dioxane (5 ml, 4M). After stirring for 16 hours the reaction mixture was evaporated. The resulting beige solid was triturated with methanol to yield 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.523 g) as a pale yellow solid. LC-MS (METHOD B): RT=0.63 minutes; 268 (M+H)+. (b) 3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine