Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)O)cc1Cl
Product: Oc1ccc2nc(-c3ccc(O)c(Cl)c3)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as an off-white solid, m.p. 254-256° C.; MS m/e 262 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N)cc2nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2nc1C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (109 mg, 0.485 mmol) in dichloromethane (3 mL) was added pyridine (90 μL, 1.2 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2,3-dimethylquinoxaline [22] (80 mg, 0.46 mmol) was added. The resulting mixture was stirred for 6 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (152 mg, 91%), single spot at Rf 0.70 (ethyl acetate). mp 225.3-225.7° C. HPLC purity 99+% (tR 2.29 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.99 (1H, d, 4=7.9. Hz), 7.85 (1H, d, J=9.2 Hz), 7.54-7.52 (2H, m), 7.40 (1H, dd, J=9.1, 2.6 Hz), 7.21 (1H, t, J=7.9 Hz), 6.95 (1H, s, N—H, 2.75 (3H, s), 2.67 (6H, s). LCMS: 360.24 (M−). FAB-MS (MH+, C17H16ClN3O2S): calcd 362.0730, found 362.0732.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:42][CH2:41][C:17]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[N:26]=[C:27]5[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][N:28]5[CH:40]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:42][CH2:41][C:17]3([CH2:18][CH2:19][N:20]([C:23]([C:25]4[N:26]=[C:27]5[CH2:32][NH:31][CH2:30][CH2:29][N:28]5[CH:40]=4)=[O:24])[CH2:21][CH2:22]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cn2c(n1)CNCC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2.5 ml) was added to a cooled (0° C.) solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.86 mmol, 1.0 equiv.) in DCM (10 ml), and the mixture was stirred for 2 h at 25° C. When the reaction was complete (TLC monitoring), the solvent was removed in vacuo in order thus to yield the desired product in the form of a yellow solid. This was used directly in the next stage without further purification.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Br)n1
Reactant: CC(=O)Nc1ccccc1
Product: Cc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 51.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-6-methyl-3-nitropyridine (108 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown viscous oil (57 mg, 51%). 1H NMR (DMSO) δ 2.42 (s, 3 H), 3.31 (s, 3 H), 7.11 (d, J=8.0 Hz, 1 H), 7.51-7.63 (m, 5 H), 7.89 (d, J=8.0 Hz, 1 H); 13C NMR δ 14.6, 23.8, 118.0, 126.1, 127.7, 128.7, 129.4, 132.1, 134.8, 148.3, 150.9, 151.1. HRMS: cal for C14H14N3 [M+H+]: 224.1188; found: 224.1184.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9](=[O:11])(=[O:10])[NH2:12])[CH:5]=[CH:6][C:7]=1[NH:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2Cl)C1

Procedure:
A solution of 3-chloro-4-fluorobenzenesulfonamide (1.0 g), tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.135 g) and N-ethyl-N-isopropylpropan-2-amine (1.246 mL) in dimethylsulfoxide (15 mL) was stirred at 115° C. for 72 hours. The mixture was concentrated, and the residue was purified on a silica gel column eluting with 60% ethyl acetate to provide the title compound.
Reaction SMILES: Br[C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[O:4].[Na+].[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[OH:34])[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([O-:27])=[O:26])(=[O:16])[CH3:15].CCO.C([O-])(=O)C>CS(C)=O>[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](=[N:33]\[O:34][C:2]([C:3]([NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[O:4])([CH3:12])[CH3:11])/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Reactant: CN(C)C(=O)NC(=O)C(C)(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NC(=O)N(C)C)c3ccco3)[C@H]2SC1
Yield: 59 %

Procedure:
This compound was prepared from 1-(2-bromo-2-methylpropionyl)-3,3-dimethylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. λmax (EtOH) 275 nm (ε 16,500), νmax (Nujol) 3260 (NH), 3700-2100 (bonded OH), 1788 (β-lactam), 1735 (acetate), 1720 (--CO2H), 1670, 1540 cm-1 (--CONH), τ (DMSO d6) 7.09 (N(Me)2), 0.97 (--CONHCO--), 8.5 (C(Me)2), 2.06, 3.28, 3.16 (furyl), 0.18 (CONH), 4.01 (7 H), 4.71 (6 H), 6.25, 6.46 (2--CH2 --), 4.97, 5.29 (3--CH2 --), 7.98 (CH3CO). Yield: 59%.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=O.C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][CH:18]2[CH2:17][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(NC3Cc4ccccc4C3)cc2)cc1
Yield: 94.4 %

Procedure:
A solution of 1.00 g (4.2 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride, 555 mg (4.20 mmol, Aldrich) of 2-indanone and 132 mg (2.10 mmol) of sodium cyanoborohydride in 25 ml of MeOH was stirred over 3A molecular sieves at 25° C. for one hour. The mixture was filtered, EtOAc was added and this was washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 1:5 EtOAc/petroleum ether) afforded 1.25 g (95%) of title compound as a tan solid: m.p. 72°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH:11]=1.[N:18]([Sn:21]([CH3:24])([CH3:23])[CH3:22])=[N+:19]=[N-:20]>>[CH3:16][C:13]1([CH3:17])[CH2:14][CH2:15][C:10]([C:3]2[CH:4]=[C:5]([C:6]3[N:18]([Sn:21]([CH3:24])([CH3:23])[CH3:22])[N:19]=[N:20][N:7]=3)[CH:8]=[CH:9][C:2]=2[NH2:1])=[CH:11][CH2:12]1
Reactant: CC1(C)CC=C(c2cc(C#N)ccc2N)CC1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CC1(C)CC=C(c2cc(-c3nnnn3[Sn](C)(C)C)ccc2N)CC1

Procedure:
The title compound was prepared from 4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-benzonitrile (as prepared in the previous step, 245 mg, 1.08 mmol), and azidotrimethylstannane (246 mg, 1.19 mmol) according to the procedure in Example 52, step (c) (363 mg, 78%). Mass spectrum (ESI, m/z): Calcd. for C15H19N5, 270.1 (M-SnMe3+2H), found 270.1.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3].O=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([BH3-])#N.[Na+].[ClH:40]>O.C(O)C>[ClH:40].[CH2:26]([O:25][C:23]([CH:22]([NH:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: C[C@H](N)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
L-Alanyl-N-(indan-2-yl)-β-alanine (2.0 g) is dissolved in a mixture of 20 ml of water and 100 ml of ethanol, 10 g of ethyl 2-oxo-4-phenylbutyrate is added, and a solution of 0.94 g of sodium cyanoborohydride in 20 ml of ethanol is added dropwise over 2 hours. The mixture is stirred at room temperature for 3 hours and then adjusted to pH 4.0 with 10% hydrochloric acid, and the ethanol is distilled off under reduced pressure. The residue is extracted with 200 ml of ethyl acetate, washed with water and dried, and the ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 2 ml of 20% ethanolic hydrochloric acid, 100 ml of ethyl ether is added, and the mixture is allowed to stand at room temperature. Thus is obtained 1.2 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-β-alanine hydrochloride as colorless amorphous powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].S(O[CH2:15][C@H:16]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)(=O)C.C(OCC)(=O)C>C1COCC1>[CH3:1][Si:2]([CH2:3][CH2:4][S:5][CH2:15][C@@H:16]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)CCS
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)CSCC[Si](C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2-trimethylsilylethanethiol (0.86 g, 6.41 mmol), synthesis described by Anderson, Ranasinghe, Palmer, and Fuchs, above) in THF (10 mL) was added sodium hydride (0.256 g, 6.41 mmol as a 60% mineral oil dispersion). The mixture was stirred for 10 minutes. Boc-homophenylalaninol mesylate (2.00 g, 5.82 mmol, synthesis described in Example 13, above) was added. The solution was stirred for 2 hours. Ethyl acetate (50 mL) was added. The solution was washed with 30 mL each of 1M HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure, giving the intermediate (S)-2-tert-butoxycarbonylamino-4-phenylbutyl trimethylsilylethyl sulfide. TLC: (5% ethyl acetate/hexane) Rf =0.22. This material was dissolved in CH2Cl2 (50 mL), cooled to -10° C., and treated with 4-chloroperbenzoic acid (3.24 g, 12.22 mmol, estimated 65% peracid content). The mixture was stirred overnight. The suspension was filtered, and saturated aqueous NaHSO3 (40 mL) and saturated aqueous sodium bicarbonate (50 mL) were carefully added to the filtrate. The organic phase was separated, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the product, Boc-Hph-β-SO2CH2CH2TMS in quantitative mass recovery from the mesylate. TLC: (30% ethyl acetate/hexane) Rf =0.49.
Reaction SMILES: [F:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([N:6]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:7](CC=CCCl)[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1)=[O:5].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CN1CCOCC1>[CH2:22]([N:6]([CH2:7][C:8]1[N:9]([CH2:29][CH:2]=[CH:3][CH2:4][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:4](=[O:5])[C:3]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:2]=1[F:1])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(C(=O)c1cccc(F)c1F)C(CC=CCCl)c1nc2ccccc2[nH]1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CCCCN(Cc1nc2ccccc2n1CC=CCN1CCCCC1)C(=O)c1cccc(F)c1F
Temperature: 90 °C
Yield: 166.5 %

Procedure:
2,3-Difluoro-N-butyl-N-[(4-chlorobut-2-enyl)-1H-benzoimidazol-2-ylmethyl)-benzamide (26 mg, 0.06 mmol) was dissolved in 0.3 mL toluene. Piperidine (10 μL, 0.1 mmol) dissolved in 0.5 mL 95/5 toluene/4-methylmorpholine was added and the reaction mixture was heated at 90° C. for 15 hours. The reaction mixture was cooled to room temperature and deposited on a 1 g silica SPE column. The column was washed with 4 mL ethyl acetate to remove impurities followed by 4 mL 10/2/1 ethyl acetate/methanol/triethylamine to elute the product to afford 24 mg N-butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(-c3cnc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.86) (0.20 g, 0.502 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.124 g, 0.552 mmol) according to the general procedure VI. Obtained as a yellow solid (0.045 g, 21%). MS (ISP) 413.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH:9]=[CH:10]N(C)C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]([NH2:41])=[NH:40])[CH:35]=[CH:34][N:33]=1>CC(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([NH:38][C:39]2[N:41]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[CH:9]=[CH:10][N:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: N=C(N)Nc1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Reaction time: 20 h
Yield: 49.1 %

Procedure:
To a solution of 6.32 g of 1-(2-chloropyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one (30 mmol) in 60 ml of 2-Propanol was added 2.52 g of sodium hydroxide (63 mmol) and 11.96 g of 1-(2-chloropyridin-4-yl)guanidine bis(trifluoroacetate) (30 mmol). The reaction mixture was heated to reflux under stirring for 20 h. After filtration, the precipitate was washed with 100 ml of n-butanol and 120 ml of iPr2O and then air-dried to yield 4.69 g of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (yield=37%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Cl:11][C:12]1[C:17]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: NCCOc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Clc1nccnc1NCCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 2-phenoxyethylamine (2.65 g, 19.3 mmol), 2,3-dichloropyrazine (2.88 g, 19.3 mmol) and K2CO3 (2.67 g, 19.3 mmol) in acetonitrile (8 mL) was stirred in a sealed tube for 12 h at room temperature, and for a further 9.5 h at 80° C. The reaction mixture was diluted with ether, filtered, and concentrated. The residue was purified by chromatography on silica gel using n-hexane/EtOAc (7:3) as eluent to give 2.36 g (49%) of the title compound as a yellowish oil that solidified on standing: mp 51-53° C.; HRMS m/z calcd for C12H12ClN3O (M)+ 249.0669. found 249.0659. Anal. (C12H12ClN3O) C, H, N
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl>[C:25]([NH:29][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (80 mg, 0.23 mmol) and t-Butylamine (17.2 mg, 0.23 mmol) in CH2Cl2 (1.2 mL) was added dropwise Ti(Oi-Pr)4 (0.27 mL, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was poured into water (150 mL) and extracted with EtOAc (100 mL*3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-78 (15 mg, 16.5%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH3:20])[CH:5]=2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:26][NH:25][CH2:24]1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH:1]1([C:4]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:7]([C:8]([N:25]3[CH2:24][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=4)([F:22])[CH2:26]3)=[O:10])=[C:6]([CH3:20])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: COc1nnc(-c2cc(C(=O)N3CC(F)(c4ccc(C#N)cc4)C3)c(C)cc2C2CC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 4-cyclopropyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 91.6) and 4-(3-fluoroazetidin-3-yl)benzonitrile (compound 43.4) were used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively. m/z (ES+) 432 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.66-13.01 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 6.86 (s, 1H), 4.60-4.38 (m, 4H), 3.91 (s, 3H), 2.82 (m, 1H), 2.34 (s, 3H), 0.94 (m, 2H), 0.71 (m, 2H).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:3][CH:2]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(C#Cc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(CCc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Yield: 85.8 %

Procedure:
To a solution of 0.20 g (0.391 mmol) of the product of Example 352 in 25 mL of methanol and 10 mL of ethyl acetate was added 0.050 g of 10% palladium on carbon. The mixture was hydrogenated in a Parr apparatus at 30 psi of hydrogen for 5 h, then filtered through Celite. The Celite pad was washed with 100 mL of methanol and 100 mL of ethyl acetate and the filtrate was concentrated in vacuo. The residue was trituratedwith ether to give 0.173 g (86%) of the carboxylic acid as a pale yellow solid. Electrospray Mass Spec: 514.2 (M-H)-.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[N:12][N:13]2[C:18]3[N:19]([CH2:22][CH3:23])[CH:20]=[CH:21][C:17]=3[C:16]([CH3:24])=[N:15][C:14]=12>C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[N:12][N:13]2[C:18]3[N:19]([CH2:22][CH3:23])[C:20]([Br:1])=[CH:21][C:17]=3[C:16]([CH3:24])=[N:15][C:14]=12
Reactant: CCn1ccc2c(C)nc3c(Br)cnn3c21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCn1c(Br)cc2c(C)nc3c(Br)cnn3c21
Reaction time: 2 h
Yield: 80 %

Procedure:
N-bromosuccinimide was added at room temperature to a solution of 1.675 g (6 mmoles) of 3-bromo-8-ethyl-5-methyl-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (prepared as described in Example 13) dissolved in 12 ml of chloroform, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with chloroform) and recrystallized from ethyl acetate to afford 1.72 g (yield 80%) of the title compound as colorless needles, melting at 135°-137° C.