Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: C1COCCN1
Reactant: Clc1ncncc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cncnc1N1CCOCC1
Temperature: 90 °C
Yield: 97 %

Procedure:
To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.200 g, 0.832 mmol) in DMF (1.333 mL) was added morpholine (0.291 mL, 3.33 mmol) followed by cesium carbonate (0.542 g, 1.664 mmol). The vial was sealed with a Teflon cap and heated at 90° C. for 80 min, then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The filtrate was concentrated, then further dried under high vacuum to afford the title compound (235 mg, 97%). ESI MS (M+H)+=292.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([C:20]#N)[CH:9]1[CH2:22][CH2:23][CH:24]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:49])C>C(OCC)C.C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[O:49])[CH:9]1[CH2:22][CH2:23][CH:24]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(CCC1C(C#N)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCC(CCC1C(C=O)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of crude 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbonitrile (7.9 g.) [prepared as described in (l) above] in dry diethyl ether (50 ml.) was added a solution of di-isobutylaluminium hydride (4.6 g.) in dry benzene (20 ml.) at 3°-7° C. The mixture was stirred at room temperature for 15 minutes and then added with stirring to aqueous 2N acetic acid solution (75 ml.) at below 15° C. The organic phase was separated, and the aqueous layer extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate and with water, dried over magnesium sulphate, and the solvents removed in vacuo to give crude 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde (7.7 g.), which was used as starting material in the following preparation (n) of ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}hepta-2,4,6-trienoate without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 37.5 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
A 6.8 g (14 mmol) quantity of 1,3-bis(4,4′-dimethyl-diphenylamino)-4-hydroxybenzene and 32 ml (0.4 mol) of epichlorohydrin (commercially obtained from Aldrich, Milwaukee, Wis.) were added to a 50 ml 3-neck round bottom flask equipped with reflux condenser, thermometer and mechanical stirrer to form a reaction mixture. The reaction mixture was stirred vigorously at 35-40° C. for 7 hours. While the reaction mixture was stirring, 2.7 g (0.04 mol) of powdered 85% potassium hydroxide and 0.7 g (5 mmol) of anhydrous sodium sulfate were added in two portions, with a temporary cooling of the reaction mixture to 20-25° C. prior to each addition. After termination of the reaction, the mixture was cooled to room temperature and filtered. The organic part of the mixture was treated with diethylether and washed with distilled water until the wash water had a neutral pH. After the organic solution was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered, the solvent was removed. The residue was purified by column chromatography (silica gel, grade 62, 60-200 mesh, 150 Å, Aldrich) using a mixture of acetone:hexane in a volume ratio of 1:4 as the eluant. Fractions containing the product were collected and the solvent was evaporated to afford 4.8 g (63%) of glycidyl ether of 1,3-bis(4,4′-dirnethyldiphenylamino)phenol (Compound 2). A 1H NMR spectrum (250 MHz, CDCl3) yielded chemical shifts, in ppm, of: 7.05-6.70 (m, 19H, Ar); 3.84 (d, J=4.0 Hz, OCH2); 2.84 (m, 1H, CH); 2.33 (dd, 1H, one of CH2 of oxirane); and 2.27 (s, 12H, CH3). An elemental analysis resulted in the following values in weight %: C 82.08; H 6.61; N 5.07, which compared with calculated values for C37H36N2O2 in weight percent of: C82.19; H 6.71; N 5.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].CI.[CH:25](OC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[N:6]([CH3:25])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OC(C)C
Reactant: Clc1ccc2c(c1)C(c1ccccc1)Nc1nnnn1-2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1c2nnnn2-c2ccc(Cl)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g of 7-chloro-4,5-dihydro-5-phenyltetrazolo[1,5-a]quinazoline in 20 ml of dimethylformamide was added 0.07 g of 50% sodium hydride. After the mixture was stirred at room temperature for 1 hour, 0.4 g of methyl iodide was added thereto. The resulting mixture was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was stirred with a small quantity of isopropyl ether, and the resulting precipitate was collected by filtration, washed successively with water and isopropyl ether, and dried to give 0.26 g of 7-chloro-4,5-dihydro-4-methyl-5-phenyltetrazolo[1,5-a]quinazoline as pale yellow crystals. Recrystallization from ethanol gave colorless scales, m.p. 282°-283° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:26]1([CH2:29][OH:30])[CH2:28][CH2:27]1>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:7]2[C:2]([O:30][CH2:29][CH:26]3[CH2:28][CH2:27]3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: OCC1CC1
Product: Fc1cc2nc(-c3cccnc3OCC3CC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Example 1, intermediate a) and cyclopropyl-methanol (CAS Reg. No. 2516-33-8). Colorless semi-solid (16%). MS (Turbo Spray): m/z=398.3 (M+H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C1COCC1.O>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:7]([NH:6][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:19]3[N:20]=[C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:22][C:18]=3[CH3:17])=[CH:32][CH:33]=2)(=[O:38])=[O:39])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C(=O)O
Temperature: 60 °C

Procedure:
Sodium bicarbonate (159 mg, 1.89 mmol) and 2-amino-6-methylbenzoic acid (95.5 mg, 0.63 mmol) are dissolved in a mixture of 1 mL of THF and 1.5 mL of water and heated to 60° C. A solution of the title C compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (200 mg, 0.55 mmol) in 1 mL of THF is then added dropwise. The mixture is heated for an additional 2 h at 60° C., after which most of the THF is removed by passing a stream of nitrogen gas over the solution. The residue is partitioned between EtOAc and 1 N aqueous HCl. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give crude product which is purified by chromatography on silica gel with an EtOAc (15%)-hexane (85%) mixture (containing 0.5% formic acid) as the eluent to give 2-methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid as a white solid: m.p. 167-170° C.; ESI-MS 479 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.C(OCC)(=O)C.CO.[NH3:24].CO>[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]1[S:10][C:9]([CH2:11][NH2:24])=[CH:8][CH:7]=1
Reactant: N
Reactant: O=Cc1ccc(Cc2cccc(Cl)c2)s1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1ccc(Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
To a solution of 5-(3-chloro-benzyl)thiophene-2-carbaldehyde described in Preparation Example 44 (1.2 g, 5.08 mmol) in 7N ammonia/methanol (40 mL) was added Raney nickel (2 g), and the solution was stirred at room temperature for 17 hours under hydrogen atmosphere. The reaction solution was filtered through Celite pad, the catalyst was removed, then, this filtrate was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=5:1), and the title compound (740 mg, 3.12 mmol, 61.4%) was obtained as a brown oil.
Reaction SMILES: [CH:1]([O:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=O.[CH2:41]([OH:48])[CH2:42][CH:43]([OH:47])[CH2:44]CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C:4]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:47][CH:43]([CH2:42][CH2:41][OH:48])[CH2:44][CH2:1][O:3]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC=O
Reactant: OCCC(O)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCCC(CCO)O1
Temperature: 25 °C
Yield: 116.6 %

Procedure:
A mixture of dilinoleyl ketone (III, 0.80 g, 1.5 mmol), 1,3,5-pentanetriol (II, 0.54 g, 4.5 mmol) and pyridinium p-toluenesulfonate (60 mg, 0.24 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×75 mL), brine (75 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in pale oil (1.1 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 75 mL) with 0-3% methanol gradient in dichloromethane as eluent. This afforded 0.75 g (79%) of pure IV as colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:11]([CH3:33])[CH:10]=2)=[N:7][CH:8]=1)[CH3:2].[OH-].[Na+].C1COCC1.Cl>CO>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[C:11]([CH3:33])[CH:10]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)O)cc3)c(C)c2)nc1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A reaction mixture of methyl 4-((1-(4-(5-ethylpyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (12.6 g), 1M aqueous sodium hydroxide solution (82 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. for 7 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: N1CCC[C@H:2]1[C:3]([OH:5])=[O:4].[Na+:9].[Cl-].[Cl-].[K+].[Mg+2].[Cl-].[Cl-].[Cl-].[Cl-].[Ca+2].[NH2:19][C@H:20]([C:23]([OH:25])=[O:24])[CH2:21]S.C1C=NC=C(C(O)=O)C=1.N[C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[NH2:19][C@H:20]([C:23]([O-:25])=[O:24])[CH2:21][CH2:2][C:3]([O-:5])=[O:4].[Na+:9].[Na+:9]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C(O)c1cccnc1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]

Procedure:
L-proline 0.24; NaCl 2.5; KH2 PO4; KCl 0.2; MgCl2×6H20 0.1; CaCl2 0.02; TRIS 6.1; L-cysteine 0.04*; FeSO4×7H2 0.001*; niacin 0.004*; glutathion 0.10*; ascorbic acid 0.02*; resumin acids 10.0; 2.6-0-dimethyl beta cyclodextrin 1.0. pH 7.6.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][CH:18]3[CH2:22][O:21]C(C)(C)[O:19]3)[CH:16]=1)=[CH:7][CH:6]=2.Cl>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][CH:18]([OH:19])[CH2:22][OH:21])[CH:16]=1)=[CH:7][CH:6]=2
Reactant: CC1(C)OCC(Cn2cc(-c3ccc4cnc(Cl)cc4c3)cn2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)isoquinoline (Preparation 29, 40 mg, 0.116 mmol) in THF (6 mL) at 0° C. was added hydrochloric acid (2.5M, 0.30 mL) and the reaction was stirred at room temperature for 16 hours. The solution was diluted with DCM, washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (23 mg, 65%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].[BH4-].[Na+].Cl>C(O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(=O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)C(O)c1ccccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
2-Oxo-2-(2-phenoxyphenyl)acetamide (4.82 g, 20.0 mmol) was dissolved in ethanol (50 ml). Sodium borohydride (0.76 g, 20.0 mmol) was added slowly under ice-cooling. After stirring for 30 minutes, the mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated to give an oil. The oil was purified by column chromatography on silica gel (eluting with n-hexane-ethyl acetate) to give the desired compound 2-hydroxy-2-(2-phenoxyphenyl)acetamide (4.3 g, 89%) as colorless crystals. The compound was recrystallized from a mixed solvent of n-hexane-methylene chloride to give colorless crystals.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:32][CH2:31][O:30][CH2:29]4)=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:4]1[C:5]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]4[CH2:32][CH2:31][O:30][CH2:29]4)=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(NC(=O)N2CCCc3cc(C4CCOC4)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Concentrated HCl (0.26 ml) was added to a solution of (racemic) N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 336, 157 mg, 0.314 mmol) in THF (1.2 ml) and H2O (0.4 ml) at room temperature. After stirring for 5 h at room temperature, sat. aq. NaHCO3 was added and the mixture extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(=O)O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
(S)-Methyl 3-(4-amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-hydroxybenzoate (35 mg, 0.07 mmol) was dissolved in 5 mL tetrahydrofuran. Lithium hydroxide in 5 mL water was added and the mixture was stirred at 50° C. for 4 h. The solvent was evaporated and the residue was re-dissolved in dichloromethane. The aqueous phase was acidified with 2N hydrochloric acid. The aqueous was further extracted with dichloromethane and was washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1 ® Purification System to obtain 25 mg (72% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=O)[CH2:3][CH2:2]2.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[N:1]12[CH2:9][C@H:5]([CH2:6][CH2:7][CH2:8]1)[C@H:4]([C:20]#[N:21])[CH2:3][CH2:2]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCN2CCCC1C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#C[C@@H]1CCN2CCC[C@H]1C2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of 2.00 g of 1-azabicyclo[3.3.1]nonan-4-one in 100 ml of dimethoxyethane, 3.65 g of p-toluenesulfonylmethylisocyanide and 1.13 g of ethanol were added, followed by cooling to 5° C. Then, 4.00 g of potassium tert-butoxide was added while keeping the internal temperature below 10° C. The mixture was stirred at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The precipitate thus formed was removed by filtration. The residue obtained by evaporation of the solvent was purified by an alumina column chromatography (eluent: chloroform:hexane=1:1). The resulting crude product was then purified by silica gel column chromatography (eluent: chloroform:methanol=20:1), whereby 1.01 g of (4R*,5R*)-1-azabicyclo[3.3.1]nonane-4-carbonitrile was obtained.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[F:23][C:24]1[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35]C)=[O:34]>>[F:23][C:24]1[CH:29]=[C:28]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: COC(=O)CCc1ccc(O)cc1F
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(OC)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1)c1ccc(OC)cc1
Yield: 71 %

Procedure:
Compound 40 was synthesized from (1Z)-2-[4-(hydroxy methyl)phenoxy]-1-(4-methoxyphenyl)ethanone O-methyloxime (0.25 g, 0.84 mmol) and methyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.2 g, 0.94 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 71.00%); Purity: 98.10%.
Reaction SMILES: [O:1]=[C:2]1[C:7](C(O)=O)=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2
Reactant: O=C(O)c1c[nH]c2cn[nH]c2c1=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2cn[nH]c12

Procedure:
4,7-Dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-6-carboxylic acid (D6) (7.0 g, 39 mmol) was suspended in Dowtherm A (250 ml) and the mixture was heated under reflux under nitrogen for 2.5 h. After cooling, the mixture was diluted with 60°-80° petrol and filtered. The precipitate was washed well with petrol and dried to give the crude product as an off-white solid (3.9 g, 74%). Recrystallisation from aqueous ethanol/ether gave the title compound as very fine needles, m.p. >320° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18](O)=[O:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a stirring solution of 3-aminopyridine (CXXV) (0.195 g, 0.2.07 mmol) in DMF (10 mL) was added 5-bromo-1H-indazole-3-carboxylic acid (CXV) (0.500 g, 0.2.07 mmol) and N,N-diisopropylethylamine (0.723 mL, 4.15 mmol). The reaction mixture was cooled to 0° C. and added with HATU (0.787 g, 2.07 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The solution was concentrated under vacuum. The residue was purified by column chromatography (1:99 MeOH[7N NH3]:CHCl3→4:96 MeOH[7N NH3]:CHCl3) to afford 5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200 g, 0.63 mmol, 30% yield) as a white solid. ESIMS found for C13H9BrN4O m/z 318.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:9](=[O:11])[CH3:10])=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccncc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
The title compound is prepared by the procedure of Example 12 using 25 g of 4-(aminomethyl)pyridine, 25.1 ml of acetic anhydride, 2.26 g of 4-dimethylaminopyridine, 80 ml of pyridine and stirring at room temperature for 68 hours. The residue is purified by column chromatography (silica gel:20% methyl alcohol/ethyl acetate) to give 3.82 g of desired product as orange crystals.