Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:43][CH:44]([CH3:46])[CH3:45])[C:7]([F:42])=[C:8]([CH:10]([C:12]2[N:13]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)O)[CH:9]=1)[CH3:2].CS([Cl:51])(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:51][CH:10]([C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([O:43][CH:44]([CH3:46])[CH3:45])[C:7]=1[F:42])[C:12]1[N:13]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: CCOc1cc(OC(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc(OC(C)C)c(F)c(C(Cl)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.5 %

Procedure:
To a solution of Intermediate 25.1 (100 mg, 0.163 mmol) in 2 mL CH2Cl2, were added DMAP (2 mg, cat.), TEA (27 μL, 0.20 mmol) and MsCl (15.2 μL, 0.196 mmol). The mixture was stirred at rt for 30 min, then TEA (27 μL, 0.20 mmol) and MsCl (15.2 μL, 0.196 mmol) were added. The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. to afford 125 mg of Intermediate 25.2 as a yellow solid, which was used in the following step without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=3)=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(Cc4ccccc4)C3)cc2)nc1
Yield: 37.4 %

Procedure:
Using a method similar to Example 345, using 3-benzyl-piperidine (0.0748 g, 0.427 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.130 g, 0.613 mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (15:1→8:1 methylene chloride:methanol), 0.0626 g (37%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2192; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.3 Hz), 7.42 (d, 2H, J=8.8 Hz), 7.28 (t, 2H, J=7.3 Hz), 7.22-7.11 (m, 5H), 7.01 (d, 1H, J=8.3 Hz), 3.62 (d, 1H, J=12.7 Hz), 3.58 (d, 1H, J=12.7 Hz), 2.98-2.88 (m, 2H), 2.55 (d, 2H, J=6.3 Hz), 2.08 (t, 1H, J=11.7 Hz), 1.96-1.81 (m, 2H), 1.80-1.69 (m, 2H), 1.59 (qt, 1H, J=4.4, 12.7 Hz), 1.11-0.98 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O.[CH3:30][N:31](C=O)C>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].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:30]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:31]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1C#N
Temperature: 120 °C
Yield: 88.6 %

Procedure:
Ethyl 4-{2-bromo-4-[3-(pyridin-2-ylamino)propoxy]phenyl}-3,3-dimethylbutanoate (500 mg) was dissolved in DMF (10 mL) and water (1.0 mL) and was treated with tris(dibenzylideneacetone)dipalladium(0) (51 mg) and bis(diphenylphosphino)ferrocene (75 mg). The reaction mixture was heated to 120° C. for 20 hours under nitrogen atmosphere. The mixture was cooled to room temperature and was filtered through Celite under vacuum. The filtrate was concentrated. The residue was dissolved in ethyl acetate and was washed with a saturated solution of ammonium chloride, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (EA/Hexane: 40/60) to give 390 mg (88.6%) of the desired compound as an oily gum. NMR spectrum was consistent for the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccncc2)n1
Yield: 23.3 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-amine (250 mg, 1.16 mmol) and phenyl chloroformate (0.60 mL, 4.65 mmol) were reacted to give phenyl 3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-ylcarbamate (90 mg, 0.27 mmol, 23%). 1H NMR (300 MHz, DMSO-d6) δ 10.15 (br s, 1H), 8.72 (d, 2H), 7.76 (d, 2H), 7.40-7.05 (m, 5H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=4)[N:29]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O>CN(C=O)C>[N:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]5[N:28]([C:30]([C:33]([F:36])([F:34])[F:35])=[N:31][N:32]=5)[N:29]=4)[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCn5cccn5)cc4)CC3)nn12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 16.97 mg, 0.42 mmol) was added to 1H-pyrazole (28.9 mg, 0.42 mmol) in DMF (2 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 20° C. for 20 minutes. 6-[4-[4-(2-Bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.21 mmol) was added and the reaction stirred at 20° C. for 1 hour. Water (25 mL) was then added and the resulting precipitate filtered off, washed with ether and dried overnight under vacuum at 50° C. to give 6-[4-[4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (66.0 mg, 68%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([OH:29])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:29][C:4](=[O:5])[C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:1][CH3:2])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: CCC(CC)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(CC)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89.4 %

Procedure:
1.48 g (9.1 mmol) of 2,2-diethylbutyryl chloride were added to a solution of 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] 1.67 g (11.3 mmol) of 4-(1-pyrrolidinyl)pyridine and 1.0 ml (7.1 mmol) of triethylamine in 10 ml of toluene, and the resulting mixture was heated under reflux for 10 hours. At the end of this time the reaction mixture was worked-up following a procedure similar to that described in Example 5, above, to give 1.09 g (89% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]([CH3:17])[N:15]=[N:16][C:12]3=[CH:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([OH:3])=O.C(Cl)(=O)C([Cl:29])=O>ClCCl>[Cl:29][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]([CH3:17])[N:15]=[N:16][C:12]3=[CH:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)=[O:3]
Reactant: CC1N=NC2=CN=C(c3ccccc3Cl)c3cc(C(=O)O)ccc3N21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1N=NC2=CN=C(c3ccccc3Cl)c3cc(C(=O)Cl)ccc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
3.5 g (0.01 mol) of 8-carboxy-6-(2-chlorophenyl)-1-methyl[1,2,4]triazolo-[4,3-a][1,4]benzodiazepine are suspended in 40 ml of dichloromethane. While cooling in ice, 2.5 g (0.02 mol) of oxalyl chloride are added dropwise, and the mixture is stirred at room temperature for 2 hours. It is then concentrated and subsequently distilled twice with anhydrous chloroform. The crystalline residue is triturated with petroleum ether and filtered off with suction. 3.7 g (100%) of 8-chlorocarbonyl-6-(2-chlorophenyl)-1-methyl[1,2,4]- triazolo[4,3-a][1,4]benzodiazepine of melting point 295°-297° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-dimethylindan-1-one (LXIV) (16.3 g, 50.9 mmol) (Harms, W. M. and Eisenbraum, E. J. Org. Prep. Proc. Int. 1972, 4, 67-72) in 56 mL of sulfuric acid was slowly added 4.18 mL of 70% nitric acid in 20 mL of sulfuric acid at 0°-5° C. After being stirred for 1 hour, the reaction mixture was poured into 600 g of ice. The precipitates was filtered and washed with water. The solids collected were dissolved in 600 mL of ethyl acetate and washed with NaHCO3 (80 mL×2), dried over magnesium sulfate, and evaporated. The residue was triturated with methanol to give 22.2 g of the title compound as yellow solids; 1H-NMR (CDCl3) δ 1.49 (s, 6H), 2.71 (s, 2H), 7.68 (d, J=8.4 Hz, 1H), 8.48 (dd, J=2.0, 8.4 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H); MS m/e 206 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[OH:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[O:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (8.0 g), ethyl 3-chloro-4-hydroxybenzoate (7.38 g), potassium carbonate (5.09 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dried to give ethyl 3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as brown crystals (9.90 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2cccnc2)no1

Procedure:
Method same as Preparation 14 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 057 mmol) and 3-pyridinesulphonylchloride (EP911333) (134 mg, 0.63 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1C=CC=CC=1.O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:10])[O:11][CH:19]2[C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)O1

Procedure:
11.94 g (70 mM) of 1-(4-chlorophenyl)-2-propanol [J. Med. Chem. 21, 454 (1978)] and 10.57 g (70 mM) of 4-nitrobenzaldehyde were dissolved in 70 ml of anhydrous benzene, then 9.56 g (70 mM) of freshly prepared anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the mixture for 3 hours. Then the mixture was refluxed for 1.5 hours, cooled, diluted with water and the layers were separated. The organic layer was first washed with water then with a solution of sodium hydrogen carbonate, dried and evaporated. The resulting crude product was recrystallized from ethanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:21]([C:28](O)=[O:29])=[N:20]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:21]3[C:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[O:19][N:20]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1noc2c1CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1noc2c1CCCC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (90 mg, 0.345 mmol) and 4,5,6,7-tetrahydrobenzo[d]isoxazole-3-carboxylic acid (75 mg, 0.449 mmol). The product was purified with flash chromatography. Yield 111 mg (78%). 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 1.69-1.83 (m, 4H), 2.77-2.83 (m, 4H), 4.25-4.43 (m, 2H), 4.52-4.61 (m, 1H), 6.63 (d, 1H), 7.37 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 7.94 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[F:1][C:2]1[C:3]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)ccc2o1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to Scheme 11, a mixture of commercially-available 5-fluoro-1,3-benzoxazol-2(3H)-one (11-1, 1.02 g, 6.66 mmol) in DCM (66.6 ml) at RT was added chlorosulfonic acid (4.46 ml, 66.6 mmol). The suspension gradually became a solution and was stirred for 18 h at RT. Following this duration, LCMS showed complete consumption of starting material. The solution was cooled to 0° C. and carefully quenched with ice chips and then partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was back-extracted with 3×20 mL DCM and 2×20 mL EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), dried over sodium sulfate and filtered. Concentration in vacuo to yield 11-2 (5-Fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonyl chloride) as a tan solid, which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[Cu](C#N)[C:18]#[N:19]>CN1CCCC1=O>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:18]#[N:19])=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: COCCOC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: COCCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 12.1 %

Procedure:
The above-described method (Example 2) was repeated to react 2-methoxyethyl 2-amino-5-bromo-3-methylbenzoate (5.00 g, 15.88 mmol) with copper cyanide (1.49 g, 16.67 mmol) in N-methylpyrrolidone at 170° C. for 6 hours. Following working up similar to Example 2 and additional extraction with ethyl acetate and washing with aqueous 5% ethylenediamine solution, 2-methoxyethyl 2-amino-5-cyano-3-methylbenzoate (0.45 g, 11.6% of theory, 95.6 area % LC) was obtained as a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][C:15](=[O:24])[CH:14]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15](=[O:24])[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][S:35]([CH3:34])(=[O:37])=[O:36])[C:18]=2[CH:19]=1
Reactant: NCCCOc1cc(=O)oc2ccc(Cl)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
4-(3-Aminopropoxy)-6-chloro-1-benzopyran-2-one trifluoroacetate salt (0.272 mmol, 0.10 g) is suspended in 2 mL of DCM. DIEA (1.36 mmol, 0.236 mL) is added followed by methanesulfonyl chloride (0.543 mmol, 0.062 g) and the reaction is stirred at ambient temperature for 4 hrs. The solvent is removed under reduced pressure and the residue is redissolved and purified by HPLC to afford the title compound (21 mg, 23%); 1H NMR (DMSO-d6, 300 MHz) δ 7.80 (1H, d, J=2.6 Hz), 7.70 (1H, dd, J=2.5, 8.75 Hz), 7.45 (1H, d, J=8.87 Hz), 7.11 (1H, brt), 5.97 (1H, s), 4.28 (2H, t, J=6 Hz), 3.16 (2H, m), 2.91 (3H, s), 2.01 (2H, m); MS (ESI, Pos.) calcd for C13H14ClNO5S m/z [M+H]=332.0, found 331.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[Br:22][C:12]1[CH:13]=[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:9]=[N:10][C:11]=1[NH2:14]
Reactant: Cc1cnccc1-c1ccc(N)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnccc1-c1cnc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To an ice cold solution of 3′-methyl-3,4′-bipyridin-6-amine (250 mg, 1.350 mmol) in DCM (4499 μL) was added NBS (264 mg, 1.485 mmol) in two portions. The reaction mixture was stirred at 0° C. for 2 h. Reaction mixture was diluted with ethyl acetate, and was washed with water, brine, dried and concentrated. Residue was treated heptane, the solid filtered to give 5-bromo-3′-methyl-3,4′-bipyridin-6-amine (350 mg, 1.325 mmol, 98% yield) as brown color solid, used in next step reaction without purification. LCMS (m/z): 264.4/266.4 (MH+), 0.32 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.12 (d, J=5.1 Hz, 1H), 5.06 (br. s., 2H), 2.32 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([OH:35])=O.C(N(C(C)C)CC)(C)C.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([NH:57][C:58]2[N:59]=[CH:60][C:61]3[CH2:67][NH:66][CH2:65][CH2:64][C:62]=3[N:63]=2)[CH:50]=[C:51]([O:55][CH3:56])[C:52]=1[O:53][CH3:54]>CN(C=O)C.CCOC(C)=O>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([N:66]1[CH2:65][CH2:64][C:62]2[N:63]=[C:58]([NH:57][C:49]3[CH:48]=[C:47]([O:46][CH3:45])[C:52]([O:53][CH3:54])=[C:51]([O:55][CH3:56])[CH:50]=3)[N:59]=[CH:60][C:61]=2[CH2:67]1)=[O:35]
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Reactant: O=C(O)c1cccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cccs2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.021 g, 0.047 mmol) in anhydrous DMF (1.5 mL) was treated sequentially with thiophene-2-carboxylic acid (0.008 g, 0.062 mmol) and diisopropylethylamine (0.025 mL, 0.095 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.015 g, 0.047 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 40% yield (0.008 g, 0.019 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[O:26]CC1C=CC=CC=1)(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[OH:26])(=[O:15])=[O:14])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(O)c1

Procedure:
A solution of (S)-3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-succinamic acid tert-butyl ester (0.92 g, 2.0 mmol) in THF (50 mL) was shaken with 20% Pd/C (0.090 g) under H2 (50 psi) for 5 h using Parr apparatus. The reaction mixture was filtered through celite and concentrated. (S)-3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained (0.85 g, 98%) as an off white solid. MS (APCI) m/z 400.1 (M−1).