Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.C(O)CCC.O.[NH2:21][NH2:22]>[N+](C)([O-])=O>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:21][NH2:22])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Reactant: NN
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: CCCCO
Product: NNc1ccc(-c2cccc(Cl)c2)nn1

Procedure:
A mixture of 6.85 g of 3-chloro-6-(m-chlorophenyl)pyridazine, 100 ml. of n-butanol and 3.05 g. of hydrazine hydrate is refluxed overnight. The solvent is removed under vacuum to give a semi-solid. The solid is dissolved in a minimum of hot nitromethane. Cooling gives 3.5 g. of amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]3([CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][C:14]([CH2:16][O:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)([OH:15])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C=O)cc3)CC2)cc1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
The compound (10.0 g) obtained in Step 3 of Example 1 and 4-hydroxybenzaldehyde (5.04 g) were dissolved in anhydrous dimethylformamide (55 mL), and to the mixture was added potassium carbonate (28.5 g) and 18-crown-6 (1.09 g) at room temperature under nitrogen atmosphere and the mixture was heated at 100° C. for five hours. After allowing to cool, insoluble matter was removed by filtration and washed with ethyl acetate (300 mL). The filtrate was cooled with ice-water and water (150 mL) was added to the mixture to be separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with water and brine successively, and dried over anhydrous sodium sulfate, followed by removal of the solvent under reduced pressure. The obtained residue was crystallized from ether and collected by filtration to obtain the titled compound (12.7 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31]>O1CCCC1.[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[CH:30]=[O:31]
Reactant: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
4,5-Dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)imidazole (29.2 g) was dissolved in tetrahydrofuran (250 ml), and 1.63N 1-butyl lithium/hexane solution (58.1 ml) was added dropwise over 20 min at from −55° C. to −60° C. The mixture was stirred at −60° C. for 30 min and N,N-dimethylformamide (58 g) was gradually added dropwise at from −55° C. to −60° C. The mixture was stirred at room temperature for 1 hr. Saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-imidazole-5-carbaldehyde (18.5 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(OC)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Yield: 73 %

Procedure:
5-Methoxy-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (33D) (0.600 mmol, 0.182 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.8 mmol, 0.198 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.660 mmol, 0.251 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-80% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) as a clear oil. (0.333 mmol, 0.205 g, 73% yield). ESI-MS: m/z 616.5 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:53][N:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:53][N:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[C:63]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:64]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg) and 1-methyl-1H-indole-2-carboxylic acid (135 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (111 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:6][C:5]1=[O:21].C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[F:23][C:2]([F:1])([F:22])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:5]1=[O:21]
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2N1CC(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 45 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 450 ml. of acetic acid was added dropwise at room temperature a solution of 13.2 g of chromium trioxide in 13.2 ml. of water. The mixture was stirred at room temperature overnight and then poured into 2 l of water. The resultant precipitate was collected by filtration, washed successively with diluted ammonia water and water, and dried to give 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone quantitatively.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.[CH2:23](I)[CH3:24]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH2:23][CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
44 mg (1.0 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.25 g (0.86 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 2.0 mL DMF and the mixture was stirred for 30 min at RT. Then 98 μL (1.2 mmol) ethyl iodide were added and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with ice water and extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O1CCCC1>C(OCC)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:8][CH2:9]1
Reactant: N#CCCCBr
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCCCN1CCOCC1
Yield: 90.2 %

Procedure:
A mixture of 10.0 g of 4-bromobutyronitrile, 14.7 g of morpholine and 40 g of tetrahydrofuran was heated under reflux for 10 hours. The reaction solution was cooled, diluted with diethyl ether, filtered, and concentrated in vacuum. Purification by vacuum distillation yielded 9.4 g of 4-morpholinobutyronitrile (boiling point: 85° C./50 Pa, yield: 91%).
Reaction SMILES: [CH:1]1([C@H:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:9][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])(=[O:12])[CH3:11]
Reactant: C[C@@H](O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H](C)C1CCCCC1
Temperature: 35 °C
Yield: 99.9 %

Procedure:
A 2 L reaction flask was charged with (R)-1-cyclohexylethanol (980 g, synthesized as above), acetic anhydride (1 Kg), and p-toluene sulphonic acid (0.4 g), and heated at 30-40° C. for 6 hours. The reaction mixture was then transferred into a separatory funnel and washed twice in 200 mL water followed by once in 200 mL 10% sodium hydroxide (aOH). The resulted organic layer was distilled at 5-10 mmHg to provide (R)-1-cyclohexylethyl acetate (1.3 Kg) (optical rotation: [α]D+2.59°; optical purity: 80.5% ee ).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](=[O:14])([O-])[O-:12].[K+].[K+].[S-2:17].[Na+].[Na+].O>CN(C=O)C.[Cu](I)I>[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][C:3]=1[S:17][C:2]1[CH:10]=[C:9]([C:11]([OH:12])=[O:14])[CH:8]=[CH:4][CH:3]=1)([OH:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc(I)c1
Reactant: [S-2]
Agent: I[Cu]I
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Sc2ccccc2C(=O)O)c1
Temperature: 100 °C
Yield: 39.1 %

Procedure:
To a solution of 3-iodobenzoic acid (24.8 g, 100.0 mmol) was dissolved in anhydrous DMF (100.0 mL) was added potassium carbonate (6.9 g, 50.0 mmol). The reaction mixture was heated to 100° C. for 5 minutes and sodium sulphide (4.3 g, 55.0 mmol) and copper iodide (1.9 g, 10.0 mmol) was added and the reaction mixture was heated to reflux under an atmosphere of nitrogen for 12 hours. Water (500.0 mL) was then added and the reaction mixture was heated to boiling with activated carbon. The carbon was filtered off while hot into an excess of 6N HCl (50.0 mL). A precipitate formed on cooling to room temperature and was collected by filtration and washed with water to afford (5.36 g, 19.5%) of the desired 3-[(carboxyphenyl)sulfanyl]benzenecarboxylic acid (GM71/7) as an off-white powder. M.S. m/z 272.73 (M−1)+. 1H NMR (300.13, d6-DMSO) 7.32-7.63 (4H, m, 4×ArH), 7.84-7.99 (4H, m, 4×ArH).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][CH:9]=[CH:8][CH:7]=2.[N:21]1[C:29]([NH2:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:30][C:29]1[N:21]=[CH:22][N:23]=[C:24]2[C:28]=1[N:27]=[CH:26][N:25]2[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1ncnc2[nH]cnc12
Reactant: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2Cc1oc(=O)c2ccccc2c1-c1ccccc1F
Yield: 64.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(bromomethyl)-4-(2-fluorophenyl)-1H-isochromen-1-one (intermediate C2, 60 mg, 0.180 mmol), 9H-purin-6-amine (48.7 mg, 0.360 mmol) and K2CO3 (49.8 mg, 0.360 mmol) to give the title compound (45 mg, 64.5%).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CC(c1ccccc1)c1ccccc1
Yield: 27.3 %

Procedure:
A solution of 3,3-diphenylpropionic acid (127 mg, 0.56 mmoles) and benzoic acid N′-isopropyl-hydrazide (100 mg, 0.56 mmoles) in DMF (5 mL) was treated with triethylamine (0.23 mL, 1.68 mmol), HOBT (91 mg, 0.67 mmoles) and EDCI (129 mg, 0.67 mmol) at room temperature for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (59 mg, 27%). LC-MS m/e 387.26 (M+H+)
Reaction SMILES: C(=O)(O[CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15](CC4C=CC=CC=4)[O:16][C:10]3=[CH:9][C:8]=2[N:7]([C:24](=[O:26])[CH3:25])[CH:6]([CH3:27])[CH2:5]1)N.C([O-])=O.[NH4+:32].[H][H]>C(O)C.[C].[Pd]>[NH2:32][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[N:7]([C:24](=[O:26])[CH3:25])[CH:6]([CH3:27])[CH2:5]1
Reactant: [H][H]
Reactant: CC(=O)N1c2cc3c(cc2C(OC(N)=O)CC1C)OC(Cc1ccccc1)O3
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC(=O)N1c2cc3c(cc2C(N)CC1C)OCO3
Reaction time: 1 h
Yield: 94.4 %

Procedure:
[Step 4] 375 mg (0.96 mmol) of the benzyl-5-acetyl-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate were dissolved in 4 mL of ethanol followed by adding 242 mg (3.84 mmol) of ammonium formate and further adding 100 mg of palladium carbon. The system was replaced with hydrogen followed by stirring for 1 hour. Following completion of the reaction, the reaction liquid was filtered with celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution and dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain 225 mg (including impurities) of 1-(8-amino-6-methyl-7,8-dihydro-[1,3]dioxolo[4.5-g]quinolin-5(6H)-yl)ethanone in the form of a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:10]=[CH:9]2.[N+](C1C=CC([O:34][C:35](=O)[NH:36][C:37]2[O:41][N:40]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=2)=CC=1)([O-])=O.CO>CN(C=O)C.ClCCl>[C:42]([C:39]1[CH:38]=[C:37]([NH:36][C:35]([NH:1][CH2:2][C:3]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:10]=[CH:9]3)=[O:34])[O:41][N:40]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)no3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
A solution of {2-[5-(2-Aminomethyl-4-fluorophenoxy)-indazol-1-yl]-ethyl}-dimethylamine (0.020 g, 0.061 mmol) in DMF (1 mL) was treated with (3-tert-buylisoxazol-5-yl)-carbamic acid 4-nitrophenyl ester (0.020 g, 0.067 mmol) (prepared according to Example 136, Step E). The mixture stirred at room temperature for 18 hours under a N2 atmosphere. The reaction mixture was chromatographed eluting with dichloromethane/ether (10:1) and then 5% MeOH in dichloromethane to afford 5.3 mg of pale yellow oil (18% yield). MS (APCI+) m/z 495 (M+1) detected; 1H NMR (400 mHz, DMSO-D6) δ 10.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.22 (d, 1H), 7.16 (m, 2H), 7.08 (m, 1H), 6.88 (m, 2H), 5.93 (s, 1H), 4.48 (t, 2H), 4.35 (d, 2H), 2.70 (t, 2H), 2.17 (s, 6H), 1.23 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C=O)C.CCOC(C)=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:3][C@@H:4]2[CH2:5][CH2:6][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 4.39 g, 109.7 mmol) was added in portions over 1 min to a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (18 g, 104.5 mmol) and 1-fluoro-4-nitrobenzene (11.1 mL, 109.7 mmol) in DMF (200 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 5 mins and then warmed to ambient temperature and stirred for 2 h. Water (750 mL) and EtOAc (300 mL) were then added and the layers were separated. The aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to leave a residue. The crude residue was purified by column chromatography, using a gradient of 10-40% EtOAc in isohexane as eluent, to give the title compound as a yellow oil (6.95 g, 23.7 mmol, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26](O)=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:52]3[CH2:53][NH:54][CH2:55][CH2:56][C:51]=3[O:50][N:49]=2)=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:29])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([N:54]2[CH2:55][CH2:56][C:51]3[O:50][N:49]=[C:48]([C:45]4[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=4)[C:52]=3[CH2:53]2)=[O:27])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)O)c(C)c1
Reactant: c1cc(-c2noc3c2CNCC3)ccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)N2CCc3onc(-c4ccncc4)c3C2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetic acid (AC31) (0.13 g, 0.31 mmol) was dissolved in dichloromethane (4 ml) and 1,1′-carbonyldiimidazole (53 mg, 0.325 mmol) was added. After the mixture had been stirred at room temperature for 1 h, 3-(pyridin-4-yl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (AM5) (62 mg, 0.31 mmol) in dichloromethane (4 ml) was added and the mixture was stirred at room temperature overnight. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (2×) and the combined organic phases were washed with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica) with ethyl acetate/hexane 20/1. Yield: 0.13 g (77%). MS, Rt=4.8 min, m/z=603.1 [MH]+
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11]CC)=[O:10])=[O:7]>O1CCOCC1.O>[Cl:23][C:21]1[CH:22]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([OH:11])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:24]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
3.44 g of 80 percent strength sodium hydride are added in portions to a stirred ice-cooled solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) in 100 ml of anhydrous dioxane. Thereafter, the mixture is stirred for 30 minutes at room temperature and for 2 hours under reflux, and the dioxane is stripped off in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of caustic alkali are added and the mixture is refluxed for 1.5 hours. The warm solution is filtered, and the residue is rinsed with H2O. The ice-cooled filtrate is then acidified to pH=1-2 with semi-concentrated hydrochloric acid, and the precipitate is filtered off under suction, washed with water and dried in vacuo at 100° C. In this manner, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid Via of melting point 234°-237° C. are obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.C([O-])([O-])=[O:27].[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:27])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2 g of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 4.1 g of Na2CO3 in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.74 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes-while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Pantoprazole with a yield of about 85% (LC purity>95%).