Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C(OCC)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 33 mg (0.046 mmol) of [(t-Bu)2P(Cl)PdCl2]2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.70 g (4.14 mmol) of Ph2NH and 0.58 g (5.17 mmol) of KO-t-Bu in 2 mL of toluene. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[CH:18]1([N:17]([CH3:16])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(C(=O)O)cc1[N+](=O)[O-])C1CCCCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and N-methylcyclohexylamine (Aldrich 10,332-2; 796.59 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 3 hours. The reaction was then allowed to return to room temperature and diluted with water. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added followed by water (15 mL). The reaction mixture was stirred at room temperature for 5 hours. After evaporation of the solvent, the solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 4 with AcOH, extracted with Et2O, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:5][C:6]=1[CH2:7][OH:8].C([O-])([O-])=O.[K+].[K+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:5]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[C:6]=1[CH2:7][OH:8]
Reactant: CCCCCCCc1nc(Cl)c(CO)[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 118.8 %

Procedure:
To a solution of 4-chloro-2-heptyl-5-(hydroxymethyl)imidazole (5.2 g, 20.7 mmol) in dry DMF (100 mL) was added anhydrous K2CO3 (4.3 g, 31.1 mmol) followed by 4-nitrobenzylbromide (5.4 g, 24.9 mmol). The solution was stirred 3-5 hours at 65°-70°. The reaction mixture was poured into a separatory funnel containing EtOAc and H2O (300 mL each). The aqueous phase was extracted with EtOAc (150 mL) and the combined organic phases were washed three times with H2O (150 mL) before being dried (MgSO4), filtered and concentrated to give 9.0 g brown crude oil. Chromatography (silica gel, 450 g; 1:1 EtOAc/hexanes) gave 1.3 g (17% overall, 35% of theoretical); m.p. 110°-115°. NMR (200 MHz, CDCl3) δ 8.20 (d, 2H, 5Hz); 7.20 (d, 2H, 5Hz); 5.35 (s, 2H); 4.45 (s, 2H); 3.10-300 (m, 1H); 2.50 (t, 2H, 5Hz); 1.75-1.50 (m 2H); 1.40-1.10 (m, 8H); 0.90-0.75 (m, 3H). Mass spec. 365.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[N:5]=1)(=O)[NH2:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[N:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C(N)=O)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a stirring solution of tert-butyl 4-(3-carbamoyl-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (985 mg, 2.0 mmol) in THF (50 mL) at room temperature under argon was added TEA (405 mg, 4.0 mmol), and was followed by addition of TFAA (840 mg, 4.0 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude product was dissolved in a small amount of DCM (˜5 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 908 mg (91%) of tert-butyl 4-(3-cyano-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.43-1.51 (m, 9H) 1.81-1.95 (m, 2H) 1.95-2.09 (m, 2H) 3.27-3.57 (m, 2H) 3.57-3.88 (m, 2H) 4.38-4.81 (m, 1H) 6.29 (s, 1H) 7.83 (d, J=8.35 Hz, 1H) 8.20 (dd, J=8.57, 2.42 Hz, 1H) 9.04 (d, J=2.64 Hz, 1H). MS (ESI) 419 (M+H-tBu).
Reaction SMILES: [C:1]([CH2:9][C:10]([O-:12])=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[CH3:13][N:14]1[C:1]([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:9][C:10](=[O:12])[N:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])CC(=O)c1ccncc1
Reactant: CNNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
thyl isonicotinoylacetate (3.01 g, 16 mmol) and 1-methyl-2-phenylhydrazine (2.03 g, 17 mmol) were suspended in water (50 ml) and glacial acetic acid (1.35 ml, 23 mmol) was added. The flask was fitted with a reflux condensor and placed in a preheated oil bath (115 C and stirred. After 4 hours, the reaction cooled to room temperature and extracted with EtOAc (2×100 ml; 50 ml), 10:1 DCM/MeOH (110 ml), and EtOAc again. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified on silica gel (DCM→20:1→10:1 DCM/MeOH→10:1→4:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, and repurified on silica gel using DCM→20:1 DCM/MeOH→5:1 DCM/2 N ammonia in MeOH). The fractions with product were collected and concentrated to give 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 70% purity, 9.2 mmol, 59%). MS (ESI pos. ion) m/z: 252 (MH+). Calc'd exact mass for C15H13N3O: 251.
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.[CH2:13]([C:15]1[O:16][CH2:17][C:18]([CH2:22]C)([CH2:20]C)[N:19]=1)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:13]([C:15]2[O:16][CH2:17][C:18]([CH3:22])([CH3:20])[N:19]=2)[CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CCC1=NC(CC)(CC)CO1
Product: COc1cc(C=C(C)C2=NC(C)(C)CO2)cc(OC)c1

Procedure:
3,5-Dimethoxybenzaldehyde was reacted with 2,4,4-triethyl-2-oxazoline to produce 2-[2-(3,5-dimethoxyphenyl)-1-methylethenyl]-4,4-dimethyl-2-oxazoline (P-1641), b.p. 171°-173° at 0.25 mm. It was administered to mice to determine the acute oral toxicity and a trained observer studied the animals for tranquilizing activity. The oral LD0 was determined to be over 5 g/kg and the animals receiving it were observed to be highly tranquilized. The compound is administered orally to animals in need of tranquilizing in a dosage of from about 100 to about 1000 mg/kg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]C)[N:3]=1.O.Cl>C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[S:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccco2)nc(N)[nH]c1=S
Temperature: 25 °C
Yield: 87 %

Procedure:
To a stirred solution of 1.1 g (4.74 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-pyrimidine-5-carbonitrile in 15 ml ethanol under argon was added 1.05 g (14.2 mmol) sodium thiolate and the mixture heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, 20 ml water added, and the mixture made slightly acidic by dropwise addition of concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dried in vacuo to afford 0.90 g (87%) 2-amino-4-furan-2-yl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 217 ([M—H]−, 100).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[Br:15]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:15][CH2:13][C:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:7]=1)=[O:14]
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(OCCCCl)c1
Reaction time: 26 h

Procedure:
A solution of the product of Step A (2.1 g) in ether (11 mL) was treated with bromine (0.53 mL) and the mixture stirred for 26 hours. The mixture was poured into saturated sodium bicarbonate solution (50 mL) and the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (50 mL) and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound (2.8 g).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl.O1CCOCC1>[Pd].CO>[CH3:2][C:3]1[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccnc1-c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccnc1-c1cccnc1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A 3-hydroxymethyl-2,3′-bipyridyl (42.3 mg, 0.227 mmole) solution containing methanol (5 ml) and 4N solution of hydrogen chloride in dry 1,4-dioxane (0.57 ml, 2.3 mmole) was hydrogenated in the presence of palladium on activated carbon catalyst (10%, 40 mg) at room temperature and ambient pressure for 3 hours. The catalyst was filtered off, washed with methanol (3×1 ml), and the combined methanolic solutions were evaporated under vacuum. The residue was dissolved in water (2 ml), sodium carbonate was added (0.1 g) and the solution was extracted with dichloromethane (3×2 ml). The combined dichloromethane solutions were dried (magnesium sulfate) and rotary evaporated at 2 mm Hg-45° C., giving the pure product (29.4 mg, 76%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:25])([CH3:24])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:27][C:28]([NH2:30])=[S:29].O>C(#N)C>[C:20]([Si:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:6][CH2:5][C:4]([C:3]1[N:27]=[C:28]([NH2:30])[S:29][CH:2]=1)([CH3:25])[CH3:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CBr
Reactant: NC(N)=S
Solvent: CC#N
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1csc(N)n1
Temperature: 25 °C
Yield: 6.1 %

Procedure:
A solution of 1-bromo-4-(tert-butyl-diphenyl-silanyloxy)-3,3-dimethyl-butan-2-one (40 g, 92.3 mmol) and thiourea (8.4 g, 110.5 mmol) in 400.0 mL of acetonitrile is heated under reflux for 4 h. After cooling the reaction mixture to room temperature, water is added and the aqueous layer is extracted with ethyl acetate; the organic layer is dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 2.3 g of 4-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-thiazol-2-ylamine as a light brown solid. Yield: 4%, over two steps; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (9H, s), 1.25 (6H, s), 3.62 (2H, s), 5.60 (2H, s), 6.15 (1H, s), 7.25-7.40 (6H, m), 7.50-7.60 (4H, m); m/z 411 [M+H].
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C@@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
To a solution of (S)-N-(5-((R)-t-butylsulfinylamino-(2-chlorophenyl)-methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (11.25 g, 21.19 mmol) in MeOH (100 mL) was added 4 M HCl in dioxane (32 mL, 128 mmol). The reaction mixture was stirred at 25° C. for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic layer was washed with aqueous NaHCO3(50 mL×2), brine (50 mL×1), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-2.5% Et3N-EtOAc) to provide (S)-N-(5-(amino(2-chlorophenyl)-methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (6.5 g, 72%, >99% ee). 1H-NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H), 7.33 (dd, J=7.9, 1.3 Hz, 1H), 7.29-7.25 (m, 1H), 7.20 (td, J=7.6, 1.7 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 6.89 (td, J=7.8, 1.7 Hz, 2H), 6.80 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.79 (s, 1H), 1.86 (bs, 2H), 1.72-1.69 (m, 2H), 1.22-1.19 (m, 2H). HPLC ret. time 2.66 min, 10-99% CH3CN, 5 min run; ESI-MS 428.1 m/z (MH+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:15])=[O:30])=[CH:12][CH:13]=2)[O:6][C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:4]1
Reactant: CSc1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CF)cc1
Temperature: -22.5 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
To a solution of 23 (334.31 g, 1.11 mol) in anhydrous dichloromethane (5.46 L) at −30° C., mCPBA (255.29 g, 1.11 mol) in anhydrous dichloromethane (3.45 L) was added drop-wise over 2 hours. The reaction mixture was stirred at −20 to −25° C. for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with saturated NaHCO3 (5.8 L) at −20° C. The organic layer was separated, washed with water (3×2 L), brine (2 L), dried over Na2SO4and concentrated to provide 358 g of crude desired product. 1H NMR (400 MHz, CD3OD) 2.80 (s, 3 H), 4.34-4.43 (m, 1H), 4.48-4.52 (m, 1H), 4.65-4.70 (m, 2H), 4.72-4.80 (m, 2H), 5.79 (d, J=8 Hz, 1 H), 7.45-7.48 (m, 2 H), 7.58-7.62 (m, 3H), 7.76-7.89 (m, 2H), 8.02-8.10 (m, 2H). The crude material was used directly in the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(N2CCCC2)nc1
Agent: Cl
Product: O=C(O)c1ccc(N2CCCC2)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1.0 g (4.85 mol) of methyl 6-(pyrrolidine-1-yl)nicotinoate was dissolved in 10 ml of conc. hydrochloric acid and stirred at 40° C. overnight. The solvent was distilled off whereby the hydrochloride of the title compound was obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].C1(=O)OC(=O)C2CCCCC12>>[CH:1](=[C:19]([C@@H:17]([C@H:15]([C@@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18])[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C1OC(=O)C2CCCCC12
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Reaction time: 0.75 h

Procedure:
A reactor was charged with 106 g (1 mole) of benzaldehyde, 270 g (1 mole) of a 70% aqueous solution of D-sorbitol and 15 g of hexahydrophthalic anhydride, and they were reacted at 20° C. with stirring. In 45 minutes after the formation of fine crystals in the mixture within the reactor, the torque of the stirrer became about 3 times as high as that at the start of the reaction. At this time, the amount of monobenzylidene sorbitol formed was 40% of theory.
Reaction SMILES: CC1[O:19][C:7]2[C:8]([O:17][CH3:18])=[C:9]3[O:16][CH:15]=[CH:14][C:10]3=[C:11]([O:12][CH3:13])[C:6]=2C(=O)C=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:19][C:7]1[CH:6]=[C:11]([O:12][CH3:13])[C:10]2[CH:14]=[C:15]([C:11](=[O:12])[CH:10]=[C:9]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:8])[O:16][C:9]=2[C:8]=1[O:17][CH3:18]
Reactant: C1CCNC1
Reactant: COc1c2occc2c(OC)c2c(=O)cc(C)oc12
Product: COc1cc(O)c(OC)c2oc(C(=O)C=C(C)N3CCCC3)cc12
Yield: 190.3 %

Procedure:
A methanolic solution of khellin (5.2 g) and pyrrolidine (2.82 g) is heated at 80° C. for 6 hr. Upon cooling, bright orange crystals precipitate from the reaction mixture. After filtration, there is obtained 6.3 g of pure title product. Silica gel TLC Rf is 0.74 in ethyl acetate. Infrared absorptions are observed at 3180, 3160, 3120, 2300, 1630, 1600, 1530, 1345, 1325, 1260, 1170, 1155, 1140, 1130, 1060, 1050, and 1030 cm-1. NMR absorptions are observed at 7.45, 6.8, 6.25, 4.05, 3.89, 3.22-3.70, 2.68, and 1.8-2.15δ. The mass spectrum exhibits peaks at 331, 300, 261, 220, 205, 177, 111, 110, 83, and 70. The carbon:hydrogen:nitrogen ratio is 65.09:6.32:4.18.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH:2]=[CH2:3]>CO.[Co]=S>[CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc([N+](=O)[O-])c1
Agent: S=[Co]
Solvent: CO
Product: C=CCOC(=O)c1cccc(N)c1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
478 g of 3-nitrobenzoic acid allyl ester are hydrogenated in 2 l of methanol at 110° C and 30-50 bars of H2 in the presence of 60 g of a cobalt sulphide paste which contains 30% of CoS3. The absorption of H2 has ceased in 2 hours. After cooling, 30 g of NaHCO3 are added to the methanol solution which contains the suspended catalyst and the mixture is stirred for 10 minutes and filtered. Distillation gives 366 g of 3-aminobenzoic acid allyl ester, boiling point 0.35 = 135° C; ND20 = 1.5657.
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:40][C:41]1[CH:49]=[C:48]2[C:44]([C:45]([CH3:57])=[N:46][N:47]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:43][CH:42]=1.Cl[C:59]1[N:60]=[C:61]([NH:68][CH:69]2[CH2:71][CH2:70]2)[C:62]2[O:67][CH:66]=[CH:65][C:63]=2[N:64]=1>C(Cl)Cl.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]>[CH:69]1([NH:68][C:61]2[C:62]3[O:67][CH:66]=[CH:65][C:63]=3[N:64]=[C:59]([NH:40][C:41]3[CH:49]=[C:48]4[C:44]([C:45]([CH3:57])=[N:46][N:47]4[C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[CH:43][CH:42]=3)[N:60]=2)[CH2:71][CH2:70]1
Reactant: Clc1nc(NC2CC2)c2occc2n1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(N)ccc12
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Product: Cc1nn(C(=O)OC(C)(C)C)c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 45.8 %

Procedure:
In a flask, RuPhos (3.63 g, 7.79 mmol) and Pd2dba3 (3.56 g, 3.89 mmol) were combined in t-AmOH (100 mL). The mixture was degassed by bubbling N2 into the solution. The mixture was heated to about 60° C. for about 30 min. Then Cs2CO3 (38.3 g, 117 mmol), tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate (16.0 g, 64.9 mmol), and 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (13.6 g, 64.9 mmol) were added in one portion. To the mixture was added t-AmOH (200 mL) and the mixture was placed under vacuum, purged with N2, and then stiffed at about 75° C. for about 15 h. The mixture was filtered through a plug of Celite®. The filtrate was concentrated and redissolved in DCM (50 mL). The mixture was purified by column chromatography (0-2.5% MeOH in DCM over 30 min on 330 g silica gel) to give a solid. The solid was dissolved in DCM (20 mL) and after about 10 min at rt, a thick precipitate formed which was collected via filtration. The solid was washed with DCM (25 mL) and dried in a vacuum oven at about 70° C. for about 12 h to give tert-butyl 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (12.5 g, 46%); LC/MS (Table 2, Method c) Rt=2.29 min.; MS m/z: 421 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.42 (dd, J=8.6, 1.8 Hz, 1H), 7.26 (s, 1H), 6.67 (d, J=2.1 Hz, 1H), 5.29 (s, 1H), 3.20-3.12 (m, 1H), 2.55 (s, 3H), 1.72 (s, 9H), 0.99-0.91 (m, 2H), 0.71-0.64 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(O)CC.CC(O)C.C(OCC)C>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([Cl:30])[CH:26]=1)[CH2:22][O:21][C:19](=[O:20])[NH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)OCc3cc(Cl)cc(Cl)c3)ccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CCCO
Product: O=C(Nc1ccc2c(c1)CCNC2)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
Starting material 46 (170 mg, 0.4 mmol) was dissolved in 5 ml propanol. Then 1 ml HCl in 2-propanol (5-6 N) was added and the mixture was stirred over night at ambient temperature. The reaction mixture was then diluted with diethyl ether, concentrated in vacuo and stirred with diethyl ether, repeatedly decanting. Finally the solid residue was filtered off and dried in vacuo at 45° C. Thus the desired product 47 was isolated as brownish crystals (46 mg, 0.1 mmol, 35%).