Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH2:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:41]([O:43][C:44](=[O:57])[C@H:45]([OH:56])[C@H:46]([NH:55][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]2)=[CH:16][CH:15]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54])[CH3:42]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
4-(3-Methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid (100 mg, 0.6 mmol, 1.0 eq.) was combined with DMF (1000 μL) and HATU (250 mg, 0.7 mmol, 1.2 eq.) and stirred at room temperature for 15 minutes. (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (TFA salt, 200 mg, 0.6 mmol, 1.0 eq.) in DIPEA (200 μL, 2.0 eq.) and DMF (1000 μL) was then added and the resulting mixture was stirred overnight at room temperature. Excess solvent was removed and the product was dissolved in AcOH/H2O (50%) and purified by preparative LC (1″ column; gradient 2-50% MeCN/H2O, 0.05% TFA, over 80 minutes; 15 mL/min flow; UV 280 nm). The fractions were collected, frozen, and lyophilized to yield the title compound (100 mg, 98% purity). MS m/z [M+H]+ calc'd for C23H24ClN3O5, 458.14. found 458.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:10](C3C=CN=C(S(C)=O)N=3)[C:5]2=[CH:4][CH:3]=1.C1(N)CCCC1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)c1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Agent: NC1CCCC1
Product: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Yield: 38.8 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylsulfinyl-4-pyrimidinyl)imidazo[4,5-b]pyridine (200 mg 0.52 mmol) and cyclopentylamine (1 ml) are heated to 80° C. for 1 h, evaporated and purified by SiO2 chromatography (acetone/cyclohexane 10/90 to 20/80) to yield the title compound as white crystals (50 mg 24%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH2:23][CH3:24])[C:3]=1[OH:25].Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH2:23][CH3:24])[C:3]=1[O:25][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1O
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 23.9 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.458 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.994 g, 4.19 mmol). Purification on 2% H3PO4 /MeOH treated silica gel eluting with a 0 & 10% EtOAc/hexane step gradient gave 0.165 g of the title compound as a white solid, mp 238-243° C. 1H NMR (DMSO-d6) δ 1.13 (t, 3 H), 1.56 (s, 3 H), 2.39 (s, 3 H), 2.65-2.70 (m, 2 H), 7.37-7.60 (m, 7 H), 8.01-8.08 (m, 3 H). mass spectrum (-ESI) m/z 593 (M-H). Anal. Calcd. for C29H23BrO7S: C, 58.50; H, 3.89; N, 0.00. Found: C, 58.91; H, 4.02; N, 0.05.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:26]([NH2:28])[CH3:27]>O1CCCC1>[CH2:26]([NH:28][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:27]
Reactant: CCN
Reactant: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Solvent: C1CCOC1
Product: CCNc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Temperature: 60 °C

Procedure:
(2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine (0.052 g; 0.15 mmol) was treated with 1 mL of a 2 M solution of ethylamine in tetrahydrofuran. The reaction vessel was tightly sealed and the reaction mixture was heated at 60° C. for 24 h. The volatile components were removed under vacuum and the crude residue was purified directly be preparative HPLC to give 0.020 g of N2-ethyl-N4-(1-phenyl-cyclohexylmethyl)-quinazoline-2,4-diamine as a white solid. LCMS m/z=361.2 (M+H)+
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>ClCCl>[CH2:31]([NH:38][C:11](=[O:13])[C@@H:10]([OH:14])[CH:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(N)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.2 9 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethane (4 mL) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (150 mL), the solution was washed with 1 N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield (S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1.Cl[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9]([NH:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1)=[O:14]
Reactant: Nc1ncc(Cl)s1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ncc(Cl)s1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 2-amino-5-chlorothiazole and methyl chlorooxoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11].Cl.Cl[CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:10]([CH3:11])=[N:9][N:8]([CH2:19][CH2:20][NH2:21])[C:7]=1[CH3:12]
Reactant: NCCCl
Reactant: Cc1n[nH]c(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nn(CCN)c(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 120 °C
Yield: 19.3 %

Procedure:
A stirred suspension of the pyrazole (200 mg, 0.78 mmol) of Example 23 and 2-chloroethylamine hydrochloride (136 mg, 1.18 mmol) in toluene (1 ml) was heated at 120° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. After cooling, the mixture was diluted with dichloromethane (30 ml), washed with 2M aqueous sodium hydroxide solution (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane:ammonia (5:95:0.5, by volume) to afford the title compound (45 mg) as white crystals, m.p. 70–72° C.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]2[CH2:11][C:12](=O)[CH2:13][CH:6]1[CH2:7][O:8][CH2:9]2)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([N:5]1[CH:10]2[CH2:11][C:12](=[N:22][OH:23])[CH2:13][CH:6]1[CH2:7][O:8][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C2COCC1CC(=O)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCCCN1C2COCC1CC(=NO)C2
Reaction time: 0.5 h

Procedure:
To a solution of 9-(n-butyl)-3-oxa-9-azabicyclo-[3.3.1]-nonan-7-one (28 g) in ethanol (150 ml) were added in turn pyridine (18.0 ml) and hydroxylamine hydrochloride (11.9 g) and the mixture was heated under reflux for 40 minutes. To the reaction solution were added water (29 ml) and potassium carbonate (57.9 g), the mixture was stirred for 30 minutes and dried over potassium carbonate. The solvent was distilled off under reduced pressure to give the crude 9-(n-butyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one oxime. This product was employed for the sebsequent reaction without any purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][O:10][C:11]2=[O:21])[CH2:3]1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][C:5](=[O:24])[C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=4)[C@@H:8]1[CH2:9][O:10][C:11]2=[O:21]
Reactant: CC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C[C@]12CCC(=O)C=C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12

Procedure:
53 mg of 3β-hydroxy-16-oxaandrost-5-en-17-one was dissolved in 2.4 ml of acetone and the solution was cooled with ice. 60 μl of Jones reagent was added dropwise to this solution under ice cooling and stirring, and the mixture was stirred for 15 minutes. 2-propanol was added to the reaction mixture and the insoluble matters were removed by filtration. The filtrate was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium bicarbonate solution, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant crude product was purified by TLC [developing solvent; chloroform: acetone (19:1)] to obtain 9 mg of 16-oxaandrost-4-ene-3,6,17-trione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[NH:20][CH3:21])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:8])([O-])=O.C1COCC1>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[NH:20][CH3:21])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Reaction time: 4 h

Procedure:
A mixture of 3-Nitro-N-(4-bromophenyl)-4-methylaminobenzamide (120 mg, 0.34 mmol), 10 ml THF, 10 ml MeOH and 30 mg 5%-Pt-on-carbon was stirred for 4 h under a hydrogen atmosphere (3.5 bar). The catalyst was removed by filtration and the mixture was concentrated and used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:33]/[C:34](=[CH:40]\[CH3:41])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:33]/[C:34](/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:40]/[CH3:41])=[O:24])=[C:15]([C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C(\CBr)C(=O)OCC
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C/C=C(/COC(=O)C1=C([C@@H]2CCCO2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC)c3csc(N)n3)C(=O)N12)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate, (0.35g) in 1-methyl-2-pyrrolidinone (4ml) was treated with a solution of ethyl (Z)-2-bromomethylbut-2-enoate, (0.16g) in 1-methyl-2-pyrrolidinone (1ml) and stirred at ambient temperature overnight. The solution was diluted with ethyl acetate and washed with water (3x), brine and then dried. After removal of solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 70, 90% ethyl acetate-hexane and then ethyl acetate. The title compound was obtained as a pale yellow foam (0.368g, 86%); vmax (CH2Cl2) 3480, 3389, 3320, 1781, 1726, 1682, 1606 and 1532cm-1 ; δH (CDCl3) 1.30 (4H, t, J 7.1Hz, overlapping M), 1.66 (1H, m), 1.97 (3H, d, J 7.3Hz), 2.35 (1H, m), 3.33 and 3.64 (2H, ABq, J 18.7Hz), 3.88 (2H, m), 4.08 (3H, s), 4.22 (2H, q, J 7.1Hz), 4.93 (1H, m), 5.05 (3H, m), 5.80 (2H, br s, exch.), 5.99 (1H, dd, J 4.8, 9.0Hz, collapses to d, J 4.8Hz on exch.), 6.83 (1H, s), 7.21 (1H, q, J 7.3Hz) and 7.73 (1H, d, J 9.0Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (580)].
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[CH2:12][OH:13])[CH2:4][CH2:3]1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]2([NH:1][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH2:4][CH2:3]2)=[C:6]([CH2:12][OH:13])[CH:7]=1
Reactant: NC1(c2ccc(Br)cc2CO)CC1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: O=C(NC1(c2ccc(Br)cc2CO)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 850 mg of 1-(1-aminocyclopropyl)-4-bromo-2-hydroxymethylbenzene and 8.5 ml of methanol was added 1.24 g of ethyl trifluoroacetate, and the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: chloroform:ethanol=30:1), to obtain 1.02 g of colorless, crystalline 4-bromo-2-hydroxymethyl-1-(1-trifluoroacetylaminocyclopropyl)benzene.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9](Br)[CH:10]=3)[CH:3]=1.C1(NC2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:3]1[C:4]2[CH2:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[CH2:16][C:14]([C:13]=2[C:12]=34)=[CH:15][CH:2]=1
Reactant: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 25 °C

Procedure:
The compound 2 (1 g, 1.747 mmol), diphenylamine (0.88 g, 5.241 mmol), sodium tert-butoxide (0.51 g, 0.5 mmol), Pd2(dba)3 [(tris(dibenzylidene acetone) dipalladium(0))] (0.08 g, 0.087 mmol), and tri(tert-butyl)phosphine (0.017 g, 0.087 mmol) in a 50 ml round bottom flask were dissolved with toluene (10 mL), and the reaction mixture was refluxed for 12 hours. After the reaction was terminated, the reaction solution was cooled to a room temperature and extracted with distilled water (100 ml). The combined organic layers were dried over MgSO4, concentrated, and purified by silica gel column chromatography. The eluate was concentrated and dried to give a material 1 represented by Formula 9 (10.9 g, yield: 70%).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([F:15])([F:16])[F:2])=[CH:11][CH:10]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)cc1
Yield: 32 %

Procedure:
The title compound is prepared in 32% yield (78 mg, a white solid) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (184 mg, 0.72 mmol, Amine-18, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[CH2:24]([O:31][C:32](=[O:47])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])=[CH:36][CH:35]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O.CCOC(C)=O.C(O)(=O)C>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:42]([CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:47])=[CH:35][CH:36]=1)([OH:46])[CH:43]([CH3:44])[CH3:45])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)OCc1ccccc1
Reactant: CC(C)C(=O)CCc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)(CCc1ccc(NC(=O)OCc2ccccc2)cc1)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 21.9 mL (156 mmol) of diisopropylamine in dry THF (100 mL) was cooled to -40° C. under nitrogen, treated dropwise with 125 mL of 1.2M n-BuLi (150 mmol), and stirred for 30 minutes. To this solution was added a solution of 22.5 g (150 mmol) of benzyl acetate in dry THF (70 mL). The mixture was stirred at -40° C. for 45 minutes and then treated with a solution of 16.2 g (50 mmol) of [4-(4-methyl-3-oxo-pentyl)-phenyl]-carbamic acid benzyl ester (prepared in Example HHHHH) at a rapid, dropwise rate. When addition was complete, the reaction mixture was stirred at -40° C. for 30 minutes. Acetic acid (50 mL) was added, and the mixture was warmed to room temperature. EtOAc and H2O were added. The organic layer was separated, washed with brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with EtOAc:hexane (40:60), to give the title compound. 1H NMR (CDCl3) δ 0.88-0.91 (t, 6 H), 1.65-1.75 (m, 2 H), 1.85-1.89 (m, 1 H), 2.46-2.61 (m, 4 H), 3.52 (s, 1 H), 5.11 (s, 2 H), 5.16 (s, 2 H), 6.55 (br s, 1 H), 7.02 (d, 2 H), 7.24-7.38 (m, 12 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)CCC>>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:13]([C:11]([N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[CH:3][CH:4]=3)[CH2:8]2)=[O:12])[CH:18]=1)(=[O:21])=[O:20]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccncc3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and 4-tributylstannanylpyridine. White solid. MS (m/e): 492.1 [M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[CH:25])[CH2:5][CH2:4]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O.CCO>C([O-])(O)=O.[Na+]>[F:1][C:2]([F:28])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[CH:25])[CH2:5][CH2:4]1
Reactant: C#CCN(C)c1cc(NC)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#CCN(C)c1cc(NC)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-propargylamino]-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.145 mmol), Na2S2O4 (127 mg and a second 150 mg portion is added after 8 h), 1 mL water and 5 mL EtOH is stirred at 55° C. for 24 h. The mixture is diluted with sat aq NaHCO3 and extracted with EtOAc. The combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]#[C:3][CH3:4].C(Cl)(=O)OCC(C)C.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:1]([NH:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1)(=[O:5])[C:2]#[C:3][CH3:4]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of but-2-ynoic acid (61 mg, 0.581 mmol) in tetrahydrofuran (3 mL) were added isobutyl chlorocarbonate (76 μL, 0.581 mmol) and 4-methylmorpholine (80 μL, 0.727 mmol), a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol) in pyridine (1.5 mL)/N,N-dimethylformamide (2 mL) was further added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (132 mg, 73%) as a pale-orange powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: COc1ccc(B(O)O)cc1C(F)(F)F
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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 26.5 %

Procedure:
A stirred mixture 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (152 mg, 0.76 mmol), 4-methoxy-3-trifluoromethylphenylboronic acid (332 mg,1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol %), potassium carbonate (418 mg, 3.03 mmol) and THF (5 ml) was degassed under a stream of nitrogen before heating in the Smith Creator microwave at 150° C. for 10 minutes. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a dark brown oil. Mixture was flash chromatographed over silica (10 g Combiflash cartridge, 7:3 heptane/ethyl acetate to 1:1 heptane/ethyl acetate) to afford 68 mg of 4-amino-6-(4-methoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile as an orange solid. 1H NMR (DMSO) δ 8.25 (d, 1H), 8.18 (m, 2H), 7.62 (s, 2H), 7.46 (d, 1H), 3.99 (s, 3H). MS m/z 339.3 (M+1).