Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[OH:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[CH:3][CH:4]=2)[N:9]([CH3:12])[C:8](=[O:13])[C:7]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
A solution of methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (100 mg, 271 μmol), Pd2dba3.CHCl3 (28 mg, 27 μmol), X-Phos (26 mg, 54 μmol) and morpholine (71 μl, 813 μmol) in 1,4-dioxane (3 ml) was treated with sodium tert-butoxide (104 mg, 1084 μmol). The reaction was stirred at 80° C. in a sealed tube. After 24 hours, the suspension was cooled to 23° C., filtered through celite (extensively washing with methanol), the filtrate concentrated in vacuo and purified by silica gel chromatography after adsorption onto silica (eluant: 10% methanol/dichloromethane+1% AcOH), affording 18 mg (18%) of 2-(4-Hydroxy-1-methyl-7-morpholino-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid as a greenish-white solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1)([O:5]C)=[O:4].Cl>O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:18]3[C:19]([N+:25]([O-:27])=[O:26])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=[CH:15][C:16]=3[N:17]=2)=[CH:11][CH:12]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(-c2nc3cc([N+](=O)[O-])c([N+](=O)[O-])cc3[nH]2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3[nH]2)cc1
Temperature: 90 °C

Procedure:
To a solution containing 4.8 g (87.6 mmole) of KOH dissolved in 200 ml of water was added 10 g (29.2 mmole) of 2-[p-carbomethoxyphenyl]-5,6-dinitrobenzimidazole (as prepared in (a) above). The resulting mixture was heated at 90° C under nitrogen for 8 hours, at which time it was allowed to cool to room temperature. The solution was then slowly acidified with 50% HCl, liberating the dinitro-acid as a light-tan precipitate. The product was collected by filtration, washed with several portions of distilled water and air-dried. Recrystallization from THF-heptane afforded golden platelets, m.p.--dec. above 350° C.
Reaction SMILES: [CH3:1][C:2]([S:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([CH3:8])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].CO>O1CCOCC1.O>[CH3:8][C:2]([S:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)SCC[C@H]1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(SCC[C@H]1CCOC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 0.43 g (1.75 mmol) of ethyl 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoate in THF/water (4/1, 6.5 mL) are added 84 mg (3.49 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. Then methanol (0.5 mL) is added and the reaction is heated to 45° C. for 16 h. Additional lithium hydroxide monohydrate (83 mg, 3.49 mmol) is added and the reaction is heated to 55° C. for 3 h. The reaction mixture is partitioned between DCM (8 mL) and water (10 mL). The aqueous layer is cooled in an ice bath, acidified with 6M aqueous HCl solution to pH 1 and extracted with DCM (3×15 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 351 mg of 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid. Yield: 92%; ES-MS: m/z 219 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.43-1.76 (9H, m), 1.96-2.16 (1H, m), 2.31 (1H, quin, J=7.31 Hz), 2.56-2.77 (2H, m), 3.37 (1H, dd, J=8.22, 7.16 Hz), 3.68-4.05 (3H, m), 7.62 (1H, br. s.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]2[O:16][CH2:15][CH2:14][CH2:13][O:7]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: OCCCO
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(OC)cc(C2OCCCO2)c1

Procedure:
3,5-dimethoxybenzaldehyde (5.00 g,30.12 mmole), 1,3-propanediol (9.15 g, 120.5 mmole), pyridinium para-toluenesulfonate (3.02 g, 12.05 mmole) and 80 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo and the remaining oil redissolved in dichloromethane and was washed with 10% NaHCO3 and H2O. The organic layer was washed over Na2SO4 and concentrated to an oil in vacuo which was purified by flash column chromatography using 2:1 hexane/ethyl acetate containing 0.5% triethylamine as eluent. (5.731 g, 85%).
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].CCN(CC)CC>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[CH:7][CH:6]=1
Reactant: C#CCCO
Reactant: CC(Br)COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)COc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29 mmol), 3-butyn-1-ol (2.6 mL, 37 mmol), CuI (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g. 5.2 mmol) in dichloromethane (40 mL) was added Et3N (6.0 mL, 44 mmol) dropwise. The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the compound, the solution was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography, eluted with hexane/ethyl acetate (2:1). 2.6 g of the title compound were obtained as a light brown solid.
Reaction SMILES: CO[CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[O:12]=[C:13]1[C:22]2[CH2:21][CH:20]([C:23]([CH3:25])=[O:24])[O:19][CH2:18][C:17]=2[C:16](=[O:26])[CH:15]=[CH:14]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:7][C:5]1[CH:6]=[C:14]2[C:15](=[CH:3][CH:4]=1)[C:16](=[O:26])[C:17]1[CH2:18][O:19][CH:20]([C:23]([CH3:25])=[O:24])[CH2:21][C:22]=1[C:13]2=[O:12]
Reactant: CC(=O)C1CC2=C(CO1)C(=O)C=CC2=O
Reactant: C=C(C=COC)O[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C1CC2=C(CO1)C(=O)c1ccc(O)cc1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
A mixture of 1-methoxy-3-trimethylsilyloxy butadiene (776 mg, 4.51 mmol) and methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (309 mg, 1.50 mmol) in 6 mL of dry toluene was stirred for 90 minutes at room temperature under argon atmosphere. The solvent was then removed in vacuo and the dried residue was dissolved in 10 mL of THF. To this solution was added 2 mL of a 4% aq. HCl solution. The combined organic layers were then washed with water and dried over MgSO4. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 180 mg (65% yield) of the titled compound (MP: 169°-170° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: COCCOCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COCCOC

Procedure:
150 mL solution of 10 g (2-methoxyethoxy)acetic acid and 1 mL conc. sulfuric acid in ethanol was heated for 3 hours under reflux, and then the solvent was removed. The resulting residue was diluted with ethyl acetate and washed with an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed, whereby 9.5 g of the title compound (colorless oil) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:18]([CH3:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCc2[nH]c3ccccc3c2C1C
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
10.2 g of 4-methyl-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester is dissolved/suspended in 300 ml xylene and the mixture is boiled for 10 minutes in a Dean-Stark apparatus to remove moisture. After cooling to 100°-110° C., 2.1 mole equivalents of sulphur are added and the mixture is boiled under reflux for 5 hours. The progress of the reaction is followed by DC. Subsequently, the xylene is evaporated in vacuo. The remainder is dissolved in chloroform and purified by chromatography (chloroform-ethanol radient) on silica to remove non-reacted sulphur. 4-Methyl-β-carbolin-3-carboxylic acid ethyl ester having a melting point of 235°-239° C. is obtained in a yield of 72%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1(B(O)O)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:19]1([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: OB(O)C1CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CCC2)cc1F
Temperature: 90 °C
Yield: 41.6 %

Procedure:
A solution of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (1.8 g, 6.2 mmol), cyclobutyl boronic acid (0.78 g, 7.5 mmol), Pd(dppf)Cl2 (0.40 g, 0.5 mmol), and 2M aqueous cesium carbonate (aq) (5 mL, 9.9 mmol) in toluene (10 ml) was degassed with argon for 10 minutes and then heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and filtered through hyflo®. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL). The organic layer was isolated, then washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was subjected to flash chromatography (Si-PPC, gradient 0% to 30%, DCM in pentane) to afford the title compound as a yellow liquid (0.504 g, 42%). 1H NMR (DMSO-d6): 8.08 (1H, t, J=8.3 Hz), 7.44 (1H, d, J=13.2 Hz), 7.28 (1H, d, J=8.5 Hz), 3.65 (1H, m), 2.33 (2H, m), 2.13 (2H, m), 1.99 (1H, m), 1.84 (1H, m).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C:16]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:17][C:18]([NH:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:39][OH:40])=[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1)#[N:14]>C1COCC1>[CH3:8][S:9]([O:40][CH2:39][C:30]1[C:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:32][C:33]2[N:24]([C:22](=[O:23])[NH:21][C:18]3[CH:17]=[C:16]([O:41][CH:42]([CH3:44])[CH3:43])[C:15]([C:13]#[N:14])=[CH:20][N:19]=3)[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (80 μL, 0.577 mmol) and methanesulfonyl chloride (38 μL, 0.488 mmol) were added to solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 164, 194 mg, 0.439 mmol) in THF (7 ml) at 0° C. The reaction mixture was stirred for approximately 2.5 h at 0° C. and filtered to remove solid impurities. The solid residue was washed with THF and the filtrate was concentrated to yield the title compound as slight yellow resin which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CO)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution (30 mL) of ethyl 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (2.85 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/l toluene solution (12.8 mL) of diisobutylaluminum hydride was added dropwise over 30 min, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a brown oil (yield 2.29 g, 91%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol), (S)-3-amino-3-phenyl-propionic acid (62 mg, 0.38 mmol) (PepTech Corp., Burlington Mass.) and sodium methoxide (19 mg, 0.35 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 15 mg. MS: (−) m/z 452.00 (M−1).
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:19][C:20]([C:23](Cl)=[O:24])=[CH:21][CH:22]=2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[O:19][C:20]([C:23](=[O:24])[NH2:1])=[CH:21][CH:22]=2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
With simultaneous introduction of ammonia, a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise to 25 ml of a saturated solution of ammonia in THF. After 45 min, the mixture was poured into ice-water and extracted with ethyl acetate, and the organic phase was washed with 1 N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.29 g (38%) of the title compound. m.p.: 259° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]1)[CH:6]=[CH:5]2.[C:31]([O:35][C:36](=O)[O:37]C(C)(C)C)([CH3:34])([CH3:33])[CH3:32]>ClCCl.CO>[CH3:32][C:31]([O:35][C:36](=[O:37])[N:17]([CH:14]1[CH2:15][CH2:16][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[NH:21][C:22](=[O:30])[CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:8]=2)[CH2:13]1)[CH2:18][CH2:19][OH:20])([CH3:34])[CH3:33]
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 36) (1 g) in dichloromethane (5 mL) and methanol (2 mL) was added di-tert-butyl-carbonate (1 g). The mixture was stirred at room temperature for 18 hours and absorbed onto silica. Purification (SiO2, methanol:dichloromethane 5:95 as eluant) gave the title compound as a solid (400 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][N:21]=1.CN1CCCC1=O.Cl>C(O)C.C(OCC)(=O)C.[OH-].[Na+]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[N:21][CH:22]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc(N)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
To a solution of benzyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (36.9 g, 97.4 mmol) in ethanol (200 mL)/1-methylpyrrolidin-2-one (50 mL) were added 1N hydrochloric acid (50 mL) and reduced iron (27.2 g, 487 mmol), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate (200 mL), and 2N aqueous sodium hydroxide solution (50 mL) was added. The insoluble material was filtered off through a celite pad, and the insoluble material was washed with ethyl acetate (1 L). Benzyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (38.3 g, 101 mmol) was treated in the same manner as above. The obtained filtrates were combined, washed with saturated brine (3×200 mL), and purified by silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure, and the crystals precipitated during concentration were collected by filtration to give the title compound (56.6 g, 82%) as a pale-orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.05 mmol) was dissolved in 8 ml toluene. 4-Chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (280 mg, 0.90 mmol) (Example B), 3-pyridineboronic acid (133 mg, 1.08 mmol), 2M sodium carbonate (2.70 ml, 5.4 mmol) and 2 ml ethanol were added and the mixture stirred at 80° C. for 6 hrs. The reaction mixture was extracted with water and two times ethyl acetate. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 9:1->0:100 gradient). The desired compound was obtained as a light yellow solid (100 mg, 42%), MS: m/e=263.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([C:6]([F:21])([F:20])[CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:19]=[C:18]3[C:5]([C:6]([F:20])([F:21])[CH2:7][CH2:8][C@@:9]43[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]4)=[CH:4][CH:3]=2)[CH:26]=[N:27][CH:28]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=N[C@@]2(CCC(F)(F)c3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCC(F)(F)c3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 28 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-4,4,5′,5′-tetrafluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.4) with 5-chloropyridin-3-ylboronic acid yielded the title compound (28% yield) as a white solid. MS (ISP): m/z=399.9 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@H:7]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]1)=[O:4].Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[O:12][CH2:11][CH2:10][N:9]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:8][C@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]2[CH2:35][CH2:36][C:31]([F:37])([F:30])[CH2:32][CH2:33]2)=[CH:15][C:16]=1[F:21]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)CN2CCC(F)(F)CC2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-{[(chloroacetyl)amino]methyl}-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (130 mg), 4,4-difluoropiperidine monohydrochloride (94 mg) and potassium iodide (9.91 mg) in THF (3.0 mL) was added potassium carbonate (248 mg), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (133 mg).