Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:4]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl.[Na+].[Cl-]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:4]([CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:3]=1
Reactant: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(O)c1ccccc1
Yield: 79 %

Procedure:
The compound of Example 5D (4.84, 13.31 mmol) in ethanol (45 mL) was heated at 65° C. with NaBH4(2.03 g, 53.42 mmol). After 1 hour Chloroform and aqueous NaCl was added. The organic phase was separated, washed with aqueous KHCO3, dried (Na2SO4), filtered and the solvent removed under reduced pressure to provide the titled compound (3.844 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13].[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13]
Reactant: CC(C)N
Reactant: Nc1c(Br)cc(S(=O)(=O)Cl)cc1Br
Solvent: O
Product: CC(C)NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 0 °C

Procedure:
4.0 G. of 4-amino-3,5-dibromobenzenesulfonyl chloride is added to a solution of 34 ml. of isopropylamine in 30 ml. of water. The resultant solution is stirred overnight at room temperature and poured onto 250 ml. of an ice/water mixture. The precipitate is filtered, washed with water and dried. The dried filtrate is recrystallized from isopropanol affording pure 4-amino-3,5-dibromo-N-isopropylbenzenesulfonamide, m.p. 181° to 183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Yield: 84.7 %

Procedure:
3.335 g (14.5 mmol) of 6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione was dissolved in 65 mL of conc. H2SO4 with stirring and cooling in an ice-H2O bath, then 2.20 g (21.76 mmol) of KNO3 (Baker, used as received) was added in portions over 10 min. with stirring. The resulting mixture was stirred at 22° C. under N2 for 20 h. then was slowly poured into ice-H2O (400 mL) with stirring. The precipitate was collected on a sintered funnel by vacuum filtration, washed with H2O (5×10 mL), and dried at 60° C. under 0.1 mmHg for 12 h affording 3.39 g (85%) of the crude 6,7-dichloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione as a grey-yellow powder. Purity: >98.5% based on HPLC analysis.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]2[CH2:21][O:22][C:23](=[O:24])[C:10]1=2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]2[CH2:21][O:22][C:23](=[O:24])[C:10]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g (10 mmol) of ethyl 4-(2-aminophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrochloride and 1.4 ml (11 mmol) of benzyl bromide are dissolved in 50 ml of absolute acetone, 1.4 g of potassium carbonate are added, and the mixture is stirred overnight at room temperature. The mixture is concentrated, water is added, and the product is filtered off under suction and recrystallized from methanol.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH3:26])=[C:22]([CH:24]=O)[N:23]=2)[CH:20]=1>C1COCC1>[I:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([CH3:26])=[C:22](/[CH:24]=[CH:9]/[C:10]#[N:11])[N:23]=2)[CH:20]=1
Reactant: Cc1c(C=O)nc2ccc(I)cn12
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(/C=C/C#N)nc2ccc(I)cn12
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a stirred suspension of cyanomethylphosphonic acid diethyl ester (619 mg) in THF (2 ml) was added NaH (60% in oil, 144 mg) at 0° C., and the mixture was stirred at same temperature for 16 h. A solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (250 mg) in THF (2 ml) was added, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, concentrate, and purified by column chromatography (hexane/EtOAc) to afford the title compound (120 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:21][O:20][C:18]([CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1)=[O:19]
Reactant: Cc1ccc(O)c[n+]1[O-]
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C)[n+]([O-])c1
Reaction time: 0.5 h

Procedure:
A solution of the pyridine N-oxide (a) (21.12 g) in DMF (450 ml) was treated with potassium carbonate (26.2 g) then, after 30 minutes, with methyl bromoacetate (16 ml), and stirred overnight. Solvent was evaporated, saturated brine (500 ml) added and the mixture extracted with chloroform (6×200 ml). The combined organic solution was dried and evaporated and the residue chromatographed (20% EtOH in EtOAc) to give a solid (18.5 g).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][OH:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.7 %

Procedure:
A solution of 2-(N-methyl-N-t-butoxycarbonylamino)ethanol (116 mg, 0.7 mmol) in methylene chloride (1 ml) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (5 ml). Diethyl azodicarboxylate (261 mg, 1.5 mmol) was then added dropwise and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured onto a column of silica and eluted with a gradient of methylene chloride/acetonitrile/methanol (70/30/0 to 70/20/10). The partially purified product was further purified by column chromatography eluting with a gradient of methylene chloride/ether/methanol (60/40/0 to 60/10/30). The pure oil was crystallised from ether, collected by filtration and washed with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-t-butoxycarbonylamino)ethoxy)quinazoline (450 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12](O)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O)(=O)C.[O:26]1[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]1=2>O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:32]1[CH:33]=[CH:34][C:27]2[O:26][CH2:30][CH2:29][C:28]=2[CH:31]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
N-Benzyloxycarbonyl-α-hydroxyglycine (10.4 g., 0.046 mole) was added to a stirred mixture of concentrated sulfuric acid (4 ml.) and glacial acetic acid (36 ml.) at 0°-5° C. followed, after five minutes, by the dropwise addition of 2,3-dihydrobenzo(b)furan (5.8 g., 0.048 mole). The reaction mixture was stirred at ambient temperature overnight and the resulting pale mauve emulsion poured into stirred ice and water to afford a gum, which was induced to solidify. The crude product was collected, washed with water, dried in vacuo, and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to provide Dl-α-benzyloxycarbonylamino-2,3-dihydro-5-benzo(b)furanyl acetic acid (5.3 g.), m.p. 121°-123° C. Recrystallization of a sample raised the m.p. to 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:12][CH2:11][Br:10])=[C:2]([NH2:1])[CH:7]=1
Reactant: BrCCBr
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Br)ccc1OCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A mixture of the product 2-amino-4-bromophenol (500 mg, 2.66 mmol), 1,2-dibromoethane (2.5 g, 13.3 mmol) and K2CO3 (1.84 g, 13.3 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 37%) as a yellow solid. LCMS: 294 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (t, J=6.0 Hz, 2H), 4.25 (t, J=5.6 Hz, 2H), 5.06 (s, 2H), 6.63 (dd, J1=2.4 Hz, J2=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.Cl>CC(O)C>[ClH:18].[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][N:15]2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc(COc2ccc3c(c2)NCC3)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(OCc5ccccc5)cc43)c2cc1OC
Yield: 80 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 80% yield from 6-benzyloxy-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2. (M.P. 249°-250° C.(dec); LC-MS: 414 (MH+); anal. RP18-HPLC RT: 5.01 min.).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)Cc1ccccc1N
Product: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12

Procedure:
164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34]>>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:20])[CH2:11]2)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3]1)=[O:34]
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: O=C(O)c1cc2ccccc2o1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3o2)CC1)C1CCc2c(O)cccc2C1
Yield: 34.7 %

Procedure:
Compound 40h was prepared following Procedure G using 39b (214 mg, 0.674 mmol) and benzofuran-2-carboxylic acid (131 mg, 0.809 mmol) to give 40h (108 mg, 35%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 0.94-0.98 (t, 3H, J=7.2 Hz), 1.60-1.68 (m, 3H), 2.14-2.65 (m, 8H), 2.77-3.03 (m, 8H), 3.87 (bs, 4H), 6.55-6.60 (m 2H), 6.89-6.93 (t, 1H, J=7.2 Hz), 7.29-7.33 (t, 1H, J=6.4 Hz), 7.36 (s, 1H), 7.42-7.45 (t, 1H, J=7.2 Hz), 7.56-7.58 (d, 1H, J=8.8 Hz), 7.70-7.72 (d, 1H, J=7.2 Hz). The free base of 40h was converted in to its HCl salt. m.p. decomp at 140° C. Anal. [C28H35N3O.2HCl.1.5H2O] C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2ccc(F)cc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(OC)=O)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4].[Cl-].[Li+].O>CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1Cc2cccc([N+](=O)[O-])c2C1
Temperature: 160 °C
Yield: 67.7 %

Procedure:
A mixture of dimethyl-4-nitroindane-2,2-dicarboxylate (4.84 g, 0.0167 mol), lithium chloride (0.84 g, 0.0198 mol), 1.1 mL water, and 18 mL dimethylsulfoxide was heated to 160° C. under nitrogen for two hours. It was then allowed to cool and the dimethylsulfoxide was removed under high vacuum. The residue was purified on silica (10%-100% CH2Cl2 in hexanes) to give 2.5 g white solid (65%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:42])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:19][CH:17]([O:16][C:15]1[CH:14]=[CH:13][C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:42])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][NH:30][CH2:29][CH2:28]4)[N:21]=2)=[CH:11][C:10]=1[C:8]#[N:9])[CH3:18]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (3 ml) was added to an ice cooled solution of 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 22; 486 mg, 1.02 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at 0° C. for 30 minutes. The solvent was evaporated and the residue co-evaporated from toluene (×2). Trituration of the residue with diethyl ether gave the title compound as a colourless solid which was filtered off and dried (485 mg). 1H NMR (400 MHz, CDCl3) δ: 1.48 (6H, d), 2.54 (3H, s), 3.09 (2H, m), 3.5 (2H, obscured by residual solvent), 4.36 (2H, s), 4.80 (1H, m), 7.08-7.15 (2H, m), 7.85 (1H, d), 8.33 (1H, d), 8.42 (1H, s), 10.20 (2H, br s). MS m/z 375 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@H:10]([CH2:26][CH2:27][C:28]#[N:29])[C:11](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:12])[CH:5]=[CH:4][N:3]=1>CC(O)C.N.[Rh]>[NH3:1].[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@@H:10]2[CH2:26][CH2:27][CH2:28][NH:29][C:11]2=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: N#CCC[C@@H](CCc1ccnc(N)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Rh]
Agent: N
Solvent: CC(C)O
Product: Nc1cc(CC[C@@H]2CCCNC2=O)ccn1
Reaction time: 72 h

Procedure:
Nitrile 10-3 (9.48 g, 24.2 mmol) was dissolved in 200 mL i-PrOH sat. with NH3.5% Rh on alumina (10.69 g) was added, and the mixture was hydrogenated on a Parr shaker at 50 psi H2 pressure. After 3 d, the reaction mixture was filtered through Celite, re-saturated with NH3, treated with fresh 5% Rh on alumina (3.00 g), and hydrogenated at 50 psi for 1 d more. After filtering through Celite, the mixture was concentrated and purified by flash chromatography (silica, CH2Cl2, then 10%, 20%, then 30% NH3 sat. EtOH/CH2Cl2) to provide the lactam 10-4 as a crystalline yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:66]=[CH:65][C:46]3[N:47]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:48]([C:50]4[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:61]([N:47]1[C:46]2[CH:65]=[CH:66][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(=O)O
Reactant: CC(C)(C)n1c(-c2cc(F)ccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of acetic acid (52 mg, 0.86 mmol) and HATU (326 mg, 0.86 mmol) in DMF (4 mL) is added triethylamine (0.12 mL, 0.86 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-N-hydroxy-benzamidine (300 mg, 0.72 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (30 mL) is added and the organics washed sequentially with saturated NaHCO3 solution (30 mL) and H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via flash chromatography (10 g silica gel, 1.5-3% MeOH/CH2Cl2) affords the title compound (43 mg, 10%). LCMS (ESMS): m/z 444.32 (M++1)
Reaction SMILES: BrC1C(OC)=C(C=CC=1C[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].C1(S)C=CC=CC=1>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Agent: Sc1ccccc1
Product: COC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and thiophenol and used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[CH:18][N:17]=1>C1COCC1>[NH:1]([C:20]1[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:26])[CH3:27])=[CH:18][N:17]=[C:16]([Cl:15])[N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cnc(Cl)nc1Nc1ccccc1
Temperature: -10 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
A solution of aniline (0.292 ml, 3.2 mmol) and triethylamine (0.447 ml, 3.21 mmol) in THF (5 ml) was added dropwise over 10 minutes to a solution of 2,4-dichloro-5-(N-isopropylcarbamoyl)pyrimidine (Method 10, 0.75 g, 3.2 mmol) in distilled THF (8 ml) at −10° C. under nitrogen. The solution was stirred at −10° C. for 1 hour and at room temperature for 2 days. Insoluble material was removed by filtration and the filtrate was diluted with ethyl acetate (20 ml). The solution was washed with water (20 ml) and saturated sodium chloride (20 ml), and then dried. Volatile material was removed by evaporation and the residue was recrystallized from DCM to give the product as a white solid (0.34 g), which was used without characterisation.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)[CH:23]=[CH:22][C:15]=2[N:16]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCC[C@@H]4O)sc3c2)ccn1
Temperature: 110 °C

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 μL), was added (1S,2S)-2-aminocyclohexanol hydrochloride (92 mg, 0.606 mmol, 3.0 eq) followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction was heated at 110° C. for 24-hours. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=398
Reaction SMILES: [Cl-].[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:12]=[N:11][C:10]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1COCC1.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>[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:9]1[N:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:12]=[N:11][C:10]=1[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Reactant: [Zn+]c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(Nc1cnc(-c2ccncc2)c(-c2ncco2)n1)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
(1,3-Oxazol-2-yl)zinc chloride (0.33M in THF, 9.3 mL, 3.06 mmol) was added to a solution of N-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide (Preparation 8, 280 mg, 1.02 mmol) in THF (2 mL) and the mixture was degassed Pd(PPh3)4 (118 mg, 0.102 mmol, 10 mol %) was added and degassing was repeated. The reaction mixture was heated to 90° C. in a sealed tube and stirred overnight. The mixture was cooled and more (1,3-oxazol-2-yl)zinc chloride (0.33M, 5.0 mL, 1.65 mmol) and Pd(PPh3)4 (90 mg, 8 mol %) were added and the mixture was degassed and heated to 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was purified by flash silica gel chromatography (dichloromethane/methanol 98:2) to give the title compound (80 mg, 26%) as a pale yellow solid.