Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:18]2[C:6](=[C:7]([CH3:21])[C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1>>[CH3:20][O:19][C:13]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[C:7]([CH3:21])=[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH:23]5[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]5)[C:18]4=[CH:17][C:16]=3[C:15]=2[CH:14]=1
Reactant: COc1ccc2[nH]c3c(C)c4ccnc(Cl)c4cc3c2c1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: COc1ccc2[nH]c3c(C)c4ccnc(NC5CC(C)(C)NC(C)(C)C5)c4cc3c2c1
Temperature: 150 °C
Yield: 71 %

Procedure:
The mixture of 1-chloro-9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (1.0 g; product known, already published) and 4-amino-2,2,6,6-tetramethylpiperidin (1.0 g) is heated at 150° C. for 21 h. Excess amino is eliminated by evaporation under reduced pressure. Water is added to the residue obtained to form a solid. This solid is filtered, washed with water, then recrystallized from xylene to yield the expected (9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazol-1-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (1.0 g, 71% yield) in the form of yellow microcrystals (melting point: 223-225° C.). NMR in agreement.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:14][O:13][N:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CON
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of 5-bromoindan-1-one (100 g, 0.47 mol) in ethanol (650 ml) under argon was added methoxylamine hydrochloride (198 g, 2.38 mol) and pyridine (125 ml). The mixture was heated under reflux for 2.5 hours, cooled to room temperature and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate and the organic phase dried and concentrated in vacuo. The crude material was recrystallised from isopropanol to afford the title compound (110 g, 97%); 1H NMR (CDCl3) 7.52 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1 Hz), 7.35 (1H, dd, J 8.3, 1 Hz), 3.97 (3H, s), 2.99 (2H, m), 2.85 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2O[C:13](=O)[C:12]([C:16]#[N:17])=[C:11]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:5]3[C:4]4[C:27](=[CH:26][CH:30]=[CH:8][CH:3]=4)[CH2:28][C:13]=3[C:12]([C:16]#[N:17])=[C:11]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c(=O)o2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 6-(4-methoxyphenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (310 mg), indanone-2 (132 mg) and NaH (40 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 202-204° C.; MS 380 (M+); IR (KBr) 2210 cm−1 (CN).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Pd].CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)=C1CCC(c2ccc(O)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reaction time: 24 h

Procedure:
10% Palladium on carbon (250 mg) was added in one portion to a stirred solution of ethyl 2-[4-(4-hydroxyphenyl)cyclohexylidene]propanoate (6.9 g, 25.3 mmol) in EtOAc (50 mL) and the reaction mixture was stirred under a hydrogen atmosphere for 24 h. The reaction mixture was filtered and concentrated in vacuo to give a solid that was recrystallised from a mixture of isohexane and EtOAc (10:1) to give the title compound (2.2 g, 32%) as a solid; 1H NMR δ (CDCl3) 1.0-1.3 (2H, m), 1.08 (3H, d), 1.2 (3H, t), 1.3-1.45 (2H, m), 1.45-1.64 (2H, m), 1.65-1.75 (1H, m), 1.77-1.9 (3H, m), 2.15-2.26 (1H, m), 2.28-2.39 (1H, m), 4.1 (2H, q), 6.68 (2H, d), 7.0 (2H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl[Si](C)(C)C.[C:23]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28](O)=[O:29])(=[O:25])[CH3:24].CN1CCOCC1.ClC(OCC(C)C)=O>ClCCl.C(O)(C)C.C(N(CC)CC)C>[C:23]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)N1CCC[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a suspension of 5.75 g (25 m mol) 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 175 ml of dichloromethane, 10.2 ml (75 m mol) triethylamine and 9.5 ml (75 m mol) chlorotrimethylsilane are added and the reaction mixture stirred at room temperature for 1 hour. To a solution of 7.86 g (50 m mol) of N-Acetyl-L-proline in 100 ml of dichloromethane at -10° C., 5.5 ml (50 m mol) of N-methylmorpholine and 6.5 ml (50 m mol) of isobutyl chloroformate are added and stirred at -10° C. for 1/2 hour. To this cold mixed anhydride mixture is added the silylated 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and the resulting mixture is stirred for 3 hrs in an ice bath and overnight at room temperature. Next, 25 ml of isopropanol is added to the reaction mixture and stirred. The reaction mixture is evaporated and the residue is triturated with ice and water. The solid is collected by filtration and washed with water, isopropanol and ether to yield 4.82 g of 6-[4-(N-Acetyl-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, m.p. 288°-290° dec. From the filtrate an additional 3.94 g of product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:9][N:4]1[CH:5]=[C:6]([C:7]#[N:8])[C:2]([NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[N:3]1
Reactant: Cn1cc(C#N)c(N)n1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])n1

Procedure:
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42, 763) (7.5 g) and 2-fluoronitrobenzene (8.4 g) were stirred in toluene (120 ml) with Adogen 464 (3.0 g) and potassium carbonate (16.5 g) at 60° C. 50% Sodium hydroxide solution (0.1 ml) was added and the mixture was heated under reflux for 2 hours. The mixture was poured on to dilute hydrochloric acid, extracted, the aqueous layer washed with toluene and the combined extracts washed twice with water. After evaporation the residue was crystallised from ethanol (750 ml) to give the title compound, m.p. 172° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:11]=[O:12]>>[CH:11]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[OH:1])=[O:12]
Reactant: C=O
Reactant: N#CCc1ccc(O)cc1
Product: N#CCc1ccc(O)c(C=O)c1
Yield: 74.5 %

Procedure:
Proceeding as in Reference 8, but substituting 4-hydroxyphenylacetonitrile (2.09 g, 15 mmol) and formaldehyde (3.6 g, 120 mmol) gave 3-formyl-4-hydroxyphenylacetonitrile (1.8 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1)[S:9]([NH:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C.O>[C:38]1([NH:44][C:45](=[O:46])[O:37][CH2:36][CH:33]2[CH2:32][CH2:31][CH:30]([CH2:29][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:9]([NH:12][C:13](=[O:28])[C:14]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[C:16]([C:24]([F:25])([F:26])[F:27])[CH:15]=3)(=[O:11])=[O:10])[CH2:35][CH2:34]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CO)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Intermediate (4) (80 mg, 140 μmole, 1.0 eq) was dissolved in acetonitrile (10 mL) and phenyl isocyanate (18 μL, 168 μmole, 1.2 eq) was added. The mixture was refluxed for 24 hours, then diluted with water and extracted repeatedly with dichloromethane. Reconstituted in dichloromethane, filtered off precipitate and purified material isolated from filtrate by RP-HPLC to give title compound. 1H NMR (400 MHz, MeOH-d4): δ 0-75-9.0 (m, 4H), 1.38-1.60 (m, 2H), 1.68-1.84 (m, 4H), 3.21 (d, 2H, J=8 Hz), 3.86 (d, 2H, J=8 Hz), 4.51 (s, 2H), 7.0 (t, 1H, J=8 Hz) 7.17-7.30 (mult, 5H), 7.33-7.7.45 (mult, 4H), 8.11 (s, 1H), 8.42 (s, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[NH:10]1[CH2:11][CH2:12][CH:7]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](O)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CCN(C2CCNCC2)C1
Reaction time: 3 h

Procedure:
(S)-tert-butyl 4-(3-hydroxypyrrolidin-1-yl)piperidine-1-carboxylate (200 mg, 0.73 mmol) was added to a solution of 4M HCl in Dioxane (4 mL) at 0-5° C. and stirring was continued at 20-35° C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by washing with diethyl ether to afford 80 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([NH2:20])=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11][C:5]=2[CH:4]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[N:26]2[N:25]=1)=O.C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[C:19]([NH:20][C:24]2[N:29]=[CH:28][C:27]3=[CH:30][CH:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[N:26]3[N:25]=2)=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH2:11][C:5]=2[CH:4]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: COc1cc2c(cc1N)CCCC(N1CCOCC1)C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CCCC(N1CCOCC1)C2
Yield: 13.2 %

Procedure:
Following a procedure analogous to 251c, 3-Methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.095 g, 0.34 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (63 mg, 0.17 mol) were converted to the title compound (25.89 mgs) as a TFA salt. H-NMR (CDCl3) δ 9.59 (broad s, 1H-TFA), 8.96 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.68-7.49 (m, 4H), 6.98-6.95 (m, 3H), 4.06-4.00 (m, 2H), 3.85 (s, 3H), 3.78-3.69 (m, 2H), 3.44-3.14 (complex series of m, 7H), 3.90-3.04 (m, 5H), 2.86 (s, 3H), 2.68-2.58 (m, 1H), 2.39-2.19 (m, 3H) 2.09-1.87 (m, 2H); LC/MS (ESI+): 577.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>C(Cl)Cl>[CH:27]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:29])[CH3:28]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCCC1CCC(=O)CC1)(C(C)C)C(C)C

Procedure:
A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate R10, 6.8 g, 52.6 mmol, (obtainable as described in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016) was dissolved in CH2Cl2 (75 mL) and treated with diisopropylethylamine (9.2 mL, 52.6 mmol) followed by tri-isopropylsilyl trifluoromethane sulfonate (TIPSTf) (15.3 g, 50.2 mmol) at −30 EC. The reaction mixture was warmed to 0 EC for 1 h. The mixture was subjected to an aqueous work-up and purified by chromatography on SiO2 to give 4-(2-triisopropylsilanyloxy-ethyl)-cyclohexanone (Intermediate R11, 11.8 g (82%). Intermediate R11 was converted via Intermediate R12 to the unsaturated aldehyde, 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13)
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C[Si](C)(C)[C:24]#[C:25][C:26]1([CH3:30])[CH2:29][O:28][CH2:27]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl-].[Na+].O.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.[Cu]I>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:24]#[C:25][C:26]4([CH3:30])[CH2:29][O:28][CH2:27]4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(O)ccc2O3)COC1
Temperature: 70 °C

Procedure:
A sealable tube was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (3.00 g, 8.62 mmol), tetrakis(triphenylphosphine)palladium (0.996 g, 0.862 mmol), copper(i) iodide (0.164 g, 0.862 mmol). To this was added trimethyl((3-methyloxetan-3-yl)ethynyl)silane (2.90 g, 17.23 mmol) followed by tetra-n-butylammonium fluoride (1 M in THF) (25.9 mL, 25.9 mmol). The resulting brown solution was flushed with argon and heated at 70° C. for 5 hours. The reaction was cooled to rt and diluted with 250 mL of water. The slurry was poured into a separatory funnel containing EtOAc (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×250 mL). In the first extraction a slight emulsion formed, this was cleared upon the addition of 50 mL of brine. The aqueous layer was then extracted with CH2Cl2 (3×200 mL). The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-100% CH2Cl2 to 10:1 methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as a brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][CH:25]([C:26]1[N:9]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:29])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(F)cc1Nc1ncccc1F
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ncccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4-fluoro-N2-(3-fluoropyridin-2-yl)benzene-1,2-diamine (81 mg, 0.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (76 mg, 0.40 mmol), HOAt (55 mg, 0.40 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) in DCM (5 mL) was stirred at 0° C. for 2 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (5 mL) and heated at 70° C. for 24 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound as an orange oil (84 mg, 61%). LCMS (Method C): RT 3.28 min [M+H]+ 375.22
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28][NH2:29].C([O-])(O)=O.[Na+]>CN(C=O)C.CO.ClCCl>[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28][NH:29][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: CC(C)=CCN
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)=CCNC(=O)c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Nitro-2-furoic acid (5 g, 0.032 mol) was dissolved in dry DMF (25 mL). To this solution was added 1,1'-carbonyldiimidazole (5.7 g, 0.035 mol). The mixture was stirred at room temperature for 15 min; an orange colored suspension was formed. 3-Methyl-2-butenyl amine hydrochloride (3.9 g, 0.032 mol) was suspended in dry DMF (15 mL) in an Erlenmeyer flask and neutralized with NaHCO3, and the amine suspension was slowly added to the 5-nitro-2-furanoic acid and 1,1'-carbonyldiimidazole reaction mixture. The reaction mixture was stirred at room temperature for 2 h. TLC (silica gel, 10% methanol-dichloromethane, Rf =0.45) indicated completion. DMF was removed on a rotary evaporator and the residue was stirred with water (800 mL) to give a yellow solid. Yield: 3.3 g (46%). mp 92°-94° C. MS m/z, 448 (2M)+, 242 (M+NH4)+, 225 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:4]2[CH:3]=1
Reactant: CI
Reactant: Oc1cc2nc(-c3ccccc3)nn2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccccc3)nn2c2ccccc12
Reaction time: 1 h

Procedure:
One gram (0.00383 mole) of the compound of Example 1 is dissolved at 60° C. in 30 ml. of dimethylformamide, the resulting solution is brought to room temperature, then 0.2 g. of a 50% oily suspension of sodium hydride is added. After 1 hour, 0.25 ml. (0.004 mole) of methyl iodide is added and the obtained mixture is stirred for 5 hours and concentrated to dryness. The obtained residue is taken up with water and recrystallized from ethanol. Yield, 0.55 g., m.p., 144°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:18][CH3:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:38][O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42]>CN(C)C=O.C(Cl)CCl>[C:40]([C@@H:41]([NH:42][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([CH:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:18][CH3:19])[CH:10]=1)[CH2:43][CH2:44][S:45][CH3:46])([O:39][CH3:38])=[O:47]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step F (0.27 g) in dimethylformamide (10 mL) was added hydroxybenzotriazole (0.16 g), EDC (0.19 g), N-methylmorpholine (0.40 mL), and (S) methione methyl ester hydrochloride (0.203 mg). After stirring for 2 h the solution was concentrated in vacuo and the residue was partitioned with water and ethyl acetate. The ethyl acetate layer was washed with saturated sodium hydrogen carbonate, 2% potassium hydrogen sulfate and saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to yield the title compound. 1HNMR (300 MHz, CDCl3) δ 7.70 (2H, s), 7.40 (2H, m), 6.95 (1H, d, J=7 Hz), 4.94 (1H, q, J=7 Hz), 4.45 (2H, s), 3.81 (3H, s), 2.82 (3H, d), 2.59 (2H, m), 2.30 (1H, m), 2.13 (1H, m), 2.12 (3H, s), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[C:34]([NH2:35])=[C:33]([NH2:36])[C:31](=[O:32])[NH:30][C:28]1=[S:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:35][C:34]1[N:27]([CH2:26][C:25]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=2)[C:28](=[S:29])[NH:30][C:31](=[O:32])[C:33]=1[NH:36][C:10](=[O:11])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)(OCc1ccccc1)C(=O)Cl
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(N)c(NC(=O)C(C)(C)OCc3ccccc3)c(=O)[nH]c2=S)cc1OCc1ccccc1
Yield: 75.3 %

Procedure:
A solution of 2-benzyloxy-2-methyl-propionyl chloride (30.70 g, 144 mmole) in THF (100 ml) was added at 0-5° C. over 15 minutes to a stirred suspension of 1-(3-benzyloxy-4-methoxy-benzyl)-5,6-diamino-2-thiouracil (40.58 g, 100 mmole) and triethylamine (31.4 ml, 225 mmole) in THF (400 ml). After 1 hour the solid was filtered off and the solution evaporated to dryness in vacuo. The residue was suspended in a mixture of diethyl ether (400 ml), water (100 ml) and saturated sodium bicarbonate solution (60 ml). After crystallization for 60 hours the solid was collected and washed with ether and water to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-5-(2-benzyloxy-2-methyl-propionylamino)-2-thiouracil (42.23 g, 75.3%). Crystallization from ethyl acetate gave mp 123-125/184-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:13])[C:9]([O:23]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:13])=[O:14])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(S(=O)(=O)Nc2ccc(Cl)cc2)cc(Cl)c2cccnc12
Agent: BrB(Br)Br
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O

Procedure:
The title compound is prepared from 5-chloro-N-(4-chlorophenyl)-8-methoxy-7-quinolinesulfonamide, which is the first title compound of Preparation 9, and 6 equivalents of BBr3 according to the procedure described in Example 18. Crystallization from Et2O/hexane/CH2Cl2 affords 0.015 g of the title compound as a red-brown solid.