Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[OH:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C(N(CC)CC)C.O>C(#N)C>[CH3:6][Si:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][O:2][C:1]([O:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:9]
Reactant: C[Si](C)(C)CCOC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O

Procedure:
2-Trimethylsilylethyl carbonochloridate (4.8 g, 26.9 mmol) was taken up in dry acetronitrile (50 mL). The solution was cooled to 0° and solid N-hydroxysuccinimide (4.0 g, 34.8 mmol) was added with vigorous stirring followed by a solution of dry triethylamine (3.2 g, 31.6 mmol) in dry acetonitrile (5 mL). The mixture was stirred at low temperature for 15 minutes, then at room temperature overnight. The mixture was poured into water (200 ml) and extracted with ether (4×50 mL). The organic extracts were combined, washed with water (2×60 mL), 1 normal hydrochloric acid (60 mL), again water (60 mL), brine (60 mL), dried with magnesium sulfate and evaporated to dryness. The residue was taken up in boiling hexane (200 mL) and the solution allowed to cool. Crystallization was completed by storage at −15° C. (yield: 1.70 g).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][O:10][C:5]2[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH:8]=[N:7][C:6]=2[CH3:9])=[CH:13][CH:14]=1)#[N:17]
Reactant: Cc1ncc(C=O)c(C)c1OCc1ccc(C#N)cc1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1OCc1ccc(C#N)cc1
Yield: 82.1 %

Procedure:
The reductive amination of 4-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (23) (2.3 g, 8.6 mmol) and 4-aminobenzonitrile (4.4 g, 37.2 mmol), as described in Example 21, gave 4-{[5-(4-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-benzonitrile (30) (2.6 g, 82% yield) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:30][C:31]1[CH:36]=[CH:35][N:34]2[C:37]([C:40](OC)=[O:41])=[CH:38][N:39]=[C:33]2[CH:32]=1.CO.C(Cl)Cl>C1COCC1>[Br:30][C:31]1[CH:36]=[CH:35][N:34]2[C:37]([C:40]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:41])=[CH:38][N:39]=[C:33]2[CH:32]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a solution of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (197.8 mg, 0.784 mmol) in anhydrous THF (3 ml) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.6 mL) under a nitrogen atmosphere at ambient temperature. The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (200 mg, 0.784 mmol) in anhydrous THF (3 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as the eluent to afford 255.6 mg of desired product as a yellow solid.
Reaction SMILES: C([O:8]C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:48]([OH:50])=[O:49])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1.O>C(OCC)(=O)C.[Pd]>[OH2:8].[C:48]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:50])=[O:49]
Reactant: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)N[C@@H](CCCCN)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
A solution of (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-carboxypropyl]-1-cyclopentylcarbonyl)tyrosine (see Preparation 9) (351 g) in ethyl acetate (1300 ml) was added to water (385 ml) and the two phase mixture hydrogenated at 414 kPa (60 psi) and room temperature over a 5% palladium-on-carbon catalyst (35 g) for 20 hours. The catalyst was filtered off, the aqueous phase separated and concentrated to low volume under reduced pressure. The viscous solution was poured into methanol (2.85 l) and stirred at room temperature for 18 hours during which time there was a slow precipitation of a solid. The solid was granulated at 5-10° C. for 2 hours, filtered, washed with methanol and dried to give the title compound as a white solid (178.1 g), m.p. 168-171° C. Found: C,51.37; H,7.47; N,9.06. C26H40N4O9S.χH2O (where χ=1) requires: C,51.81; H,7.02; N,9.30%.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:9][CH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@H:2]1[OH:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1

Procedure:
A mixture of 1,1-dimethylethyl(trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-d)] (0.023 mol) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried, yielding 4 g of 1,1-dimethylethyl(trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 42, mp. 178° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:8][CH:9]=[CH:10][C:2]1=2.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7](/[CH:11]=[CH:12]/[C:13]([N:30]=[N+:31]=[N-:32])=[O:15])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: O=C(O)/C=C/c1cccc2c1OCCO2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc2c1OCCO2
Reaction time: 16 h
Yield: 84.5 %

Procedure:
(E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acrylic acid (5 g, 24.25 mmol), diphenylphosphoryl azide (4.96 mL, 23.04 mmol), and Et3N (6.76 mL, 48.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give 4.5 g of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acryloyl azide as a yellow solid, which was taken into PhCH2Ph (50 mL). The resulting solution was slowly heated to 80° C. for 1 h and then to reflux for 3 h. After cooling to rt, the solid was collected washing with benzene to give 3.5 g of the desired product 2,3-dihydro-[1,4]dioxino[2,3-f]isoquinolin-7-ol as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 4.37 (m, 4H), 6.83 (d, J=7.09 Hz, 1H), 7.02 (d, J=8.80 Hz, 1H), 7.12 (d, J=7.34 Hz, 1H), 7.79 (d, J=8.80 Hz, 1H); MS: (M+H)+ 204.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]O)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+].Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]2[S:43][C:42]3[N:44]4[C:35](=[CH:36][N:37]=[C:38]4[CH:39]=[CH:40][CH:41]=3)[CH:34]=2)=[O:32])[CH2:26][CH2:25]1.S([O-])(=O)(=O)C>C(OCC)C.C(O)C.O.C(N(CC)CC)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:31]([C:33]3[S:43][C:42]4[N:44]5[C:35](=[CH:36][N:37]=[C:38]5[CH:39]=[CH:40][CH:41]=4)[CH:34]=3)=[O:32])[CH2:28][CH2:29]2)=[CH:11][CH:12]=1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: OCCCc1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=C(NC1CCN(CCCc2ccc(F)cc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
Under nitrogen gas, 0.47 ml (6.07 mM) of methane-sulfonyl chloride was added to a solution of 0.62 g (4.02 mM) of 3-(4-fluorophenyl)propanol and 1.1 ml (7.89 mM) of triethylamine in diethyl ether (8 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 1 hour. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the reaction mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to recover the crude mesylate. This crude product was not purified but used as it was in the next reaction. To a solution of 0.75 g (2.00 mM) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mM) of triethylamine in ethanol (8 ml) was added 0.94 g (<4.02 mM) of the above crude mesylate at room temperature and the mixture was refluxed under nitrogen for 16 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and concentrated. The crude product thus obtained was purified by column chromatography (methanol/ethyl acetate 20-30-40%) and recrystallization from ethyl acetate-ethanol to provide the title compound as red-purple crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1cccc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cccc(Cl)c3)cc2)c1C
Yield: 40.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)-palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(3-chlorophenylsulfanyl)-benzene (0.25 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3-chloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.1 g, 40%) as a solid. MS calcd. for C26H21ClFO2S [(M+H)+] 451, obsd. 451.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Reaction time: 0.05 h
Yield: 53.8 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 5 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (182 mg, 0.91 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 57 mg (53%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.9 (m, 9H), 6.55 (d, 1H, J=8 Hz), 6.35 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.75 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 1753 and 1678. MS (FD) m/e 464.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:22]>>[Br:22][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
[3-amino-5-(trifluoromethyl)phenyl]methanol (900 mg, 4.71 mmol) (Step A, Example 24) was suspended in CHBr3 (9 mL), and t-butyl nitrite (600 μL, 5.04 mmol) was added dropwise by syringe. The reaction was heated slowly to 80° C. and was maintained at this temperature for 10 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 20% EtOAc/hexanes (2 columns) to afford [3-bromo-5-(trifluoromethyl) phenyl]methanol. Rf=0.31 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.76 (d, J=5.5 Hz, 2H), 1.86 (t, J=5.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CCN(CC)CC.FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN(C=O)C>[CH:32]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[S:5][C:4]3[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=3[C:2]=2[Br:1])=[CH:12][CH:11]=1)([CH3:34])[CH3:33]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Oc1ccc(-c2sc3ccccc3c2Br)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(-c2sc3ccccc3c2Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 3-bromo-2-(4-hydroxyphenyl)benzo[b]-thiophene (9.4 g, 30.8 mmol) in 50 mL of dry DMF was treated with Et3N (6.3 g, 61.6 mmol) and cooled to 0° C. To this was added in a dropwise manner 14.2 g (46.2 mmol) triisopropylsilyl trifluoromethanesulfonate. The cooling bath was removed and the reaction allowed to stir at ambient temperature for 2 h before pouring into 100 mL brine. This was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (2×100 mL), dried over MgSO4 and concentrated under reduced pressure to 4.8 g of an oil. The crude product was purified by chromatography (SiO2 ; hexanes) to recover 11.7 g (25.4 mmol, 82%) of the desired product as a white solid.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:19]=[CH:18][C:17]=3[N+:29]([O-])=O)[CH:13]=2)=[O:7])[CH2:4][CH2:3]1.[CH3:34]O>[Pd].C(O)C>[CH:2]1([NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([N:14]3[C:15](=[O:32])[C:16]4[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[CH:21]=4)[N:29]=[CH:34]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@@H]2CCCN2)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3)cc2c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2S)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (2.05 g) and 10% palladium on carbon (0.2 g) were stirred in ethanol (40 ml) and methanol (20 ml) under an atmosphere of hydrogen gas for 19 hours at room temperature. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated. The residue was dissolved in ethanol (40 ml) and stirred with triethylorthoformate (2.16 ml) and glacial acetic acid (0.124 ml) at 80° C. for 3 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 20% methanol/ethyl acetate followed by 20% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (AZ12299441) (0.837 g) as a cream coloured foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.49 (m, 1H), 1.61-1.76 (m, 2H), 1.85 (m, 1H), 2.15 (s, 3H), 2.85 (m, 3H), 3.42 (m, 1H), 3.95 (d, 2H), 7.52 (m, 2H), 7.58 (s, 1H), 7.73 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]1=[O:15]>C(O)C.[Pd]>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]1=[O:15]
Reactant: CCOC(=O)C=Cc1ccn(C)c(=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccn(C)c(=O)c1
Yield: 101.9 %

Procedure:
Ethyl β-(N-methyl-2-oxo-4-pyridyl)acrylate (26.28 g) in ethanol (170 ml) was hydrogenated over 5% palladium on charcoal (0.25 g) at 350 KPa (50 psi), with gentle warming, until theoretical uptake had been exceeded. The reaction mixture was filtered through diatomaceous earth and evaporated under reduced pressure to give ethyl β-(N-methyl-2-oxo-4-pyridyl)propionate as an oil (27.03 g) which was sufficiently pure for the next stage of the reaction sequence.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][C:19]2[N:18]=[N:17][C:16]([Cl:15])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=2)=[C:7]([Cl:13])[CH:6]=1
Reactant: COC(=O)Cc1cc(C)c(O)c(Cl)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COC(=O)Cc1cc(C)c(Oc2cc(C(C)C)c(Cl)nn2)c(Cl)c1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A solution of 3-chloro-4-hydroxy-5-methyl-phenyl)-acetic acid methyl ester (6b) (909 mg, 0.004 mol) in anhydrous dimethyl sulfoxide (8 mL) under argon at room temperature was treated with 3,6-dichloro-4-isopropyl pyridazine (7) (1.2 g, 0.006 mol), anhydrous potassium carbonate (1.15 g, 0.008 mol) and copper (I) iodide (239 mg, 0.001 mol). The reaction mixture was heated to 90° C. overnight. At this time, the reaction mixture was cooled to room temperature, poured onto a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography using silica gel eluted with 10% ethyl acetate in petroleum ether to afford [3-chloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-5-methyl-phenyl]-acetic acid methyl ester (8b) (1.2 g, 78%) as a yellow solid; EI(+)-HRMS m/z calcd for C17H18Cl2N2O3 (M+) 369.0767, found 369.0766. Molecular Weight=369.2506; Exact Mass=368.0694
Reaction SMILES: Cl.[F:2][C:3]1([F:11])[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1.F[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25]>CCO>[F:2][C:3]1([F:11])[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:15][C:14]=2[N+:24]([O-:26])=[O:25])[CH2:5][CH2:4]1
Reactant: NCC1CCC(F)(F)CC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1

Procedure:
Following the same procedure as in Step C of Example 4 using [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (210 mg, 1.12 mmol), methyl (4-fluoro-3-nitrophenyl)carbamate (200 mg, 0.934 mmol) and TEA (0.390 mL, 2.80 mmol) in 10 mL of EtOH. The crude product was purified by silica gel flash chromatography using 5% ether/DCM as eluent. Yield: 200 mg (62%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.34-1.47 (m, 2H), 1.65-1.75 (m, 2H), 1.78-1.85 (m, 1H), 1.90-1.93 (m, 1H), 1.94-1.97 (m, 1H), 2.10-2.21 (m, 2H), 3.23 (dd, J=6.64, 5.66 Hz, 2H), 3.78 (s, 3H), 6.48 (br.s, 1H), 6.83 (d, J=9.18 Hz, 1H), 7.66 (br.s, 1H), 8.05 (br.s, 1H), 8.07 (d, J=2.54 Hz, 1H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][C:21]([NH:23][C:24]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:22][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][S:34]([OH:37])(=O)=[O:35]>CO>[CH3:33][S:34]([NH2:16])(=[O:37])=[O:35].[CH3:33][S:34]([NH2:16])(=[O:37])=[O:35].[CH:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][C:21]([NH:23][C:24]([CH:26]5[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]5)=[O:25])=[CH:22][C:17]=4[N:16]=3)=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)O
Agent: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)C1CCCCC1
Solvent: CO
Product: CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11 (0.100 g, 0.225 mmol) in MeOH (5 ml), methanesulfonic acid (0.050 ml) was added and stirred at room temperature for 2 h. The solvents were removed under reduced pressure and acetone and ether were added. The solid was collected by filtration to give the product 12 (0.075 g, 52%). M.p. 258-268° C., 1H NMR (DMSO-d6, 500 MHz): δ 11.49 (1H, brs, NH), 10.25 (1H, brs, NH), 8.79 (1H, s), 8.165 (2H, d, J=9.0 Hz), 7.87 (2H, d, J=9.0 Hz), 8.78 (1H, s), 2.40 (6H, s), 2.37 (2H, m), 1.91-1.20 (20H, m); EIMS m/z: 541.1 (M+CH3SO3H), 446.5 (M+1); Anal. (C28H39N5O8S2×2.20H2O) C, H, N, S