Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH2:12][O:13][C:14]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([O:22][CH3:23])=[N:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:24][Si:25]([CH3:39])([CH3:38])[CH2:26][CH2:27][O:28][CH2:29][N:30]1[C:34](B(O)O)=[CH:33][CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[CH3:23][O:22][C:17]1[CH:18]=[C:19]([C:14]([O:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[N:3][C:2]=2[C:34]2[N:30]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:39])([CH3:38])[CH3:24])[N:31]=[CH:32][CH:33]=2)=[CH:15][N:16]=1)[CH:20]=[O:21]
Reactant: COc1cc(C=O)c(OCc2c(Cl)ncc3ccccc23)cn1
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2c(-c3ccnn3COCC[Si](C)(C)C)ncc3ccccc23)cn1
Temperature: 125 °C
Yield: 40.8 %

Procedure:
To a mixture of 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (18 mg, 0.05 mmol, 1 equiv), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-ylboronic acid (20 mg, 0.08 mmol, 1.5 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.2 equiv), K2CO3 (30 mg, 0.22 mmol, 4 equiv) in a 5 mL microwave tube were added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)isoquinolin-4-yl)methoxy)isonicotinaldehyde (10 mg, 38%) as a white solid. LRMS (M+H+) m/z 491.1.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[Li]CCCC.N#N.CCOCC.[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][C@H:29]([CH:32]([OH:33])[C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: c1cnc2ncoc2c1
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: -45 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Alternative procedure: To a stirred solution of the oxazolo[4,5-b]pyridine (12 g, 100 mmol) in THF (300 ml) was added n-BuLi (1.6M solution in 62.5 ml of hexane) drop wise under N2 at −78° C. After 1 hour, MgBr.Et2O (25.8 g, 100 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 hour before being treated with (S)-(1-formyl-propyl)-carbamic acid tert-butyl ester (11.46 g, 60 mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (S)-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (14.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12](C)([O-:14])C.[Br-].O1CCOC1CP(CCCC)(CCCC)CCCC.Cl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][CH:12]=[O:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: O=CC=Cc1cc(Br)cc(Br)c1
Temperature: 1 °C
Reaction time: 2 h

Procedure:
3,5-dibromobenzaldehyde (16.1 g, 61.0 mmol) was added to a cold (ice-water bath) solution of tert-butoxide (13.0 g, 116 mmol), (1,3-dioxolan-2-ylmethyl)tri-n-butylphosphine bromide salt (4.5 M, 32 cm3, 144 mmol) in 400 cm3 of ether under argon. The mixture was stirred at 0-2° C. for 2 h. 1.0 M HCl(aq) (300 cm3) was added to the mixture. The reaction was gradually warmed to room temperature and stirred at room temperature for 21 h. The two layers were separated. The aqueous layer was extracted with ether (3×200 cm3). The organic layer and the ether extracts were combined, washed with brine (1×300 cm3) and dried over anhydrous magnesium sulfate. The solvents were completely removed to leave a yellow solid. The solid was purified by column chromatography of silica gel using ethyl acetate-light petroleum (40-60° C.) as eluent to give 3.36 g (19%) of A-1 as a colourless solid; δH (200 MHz; CDCl3) 6.68 (1 H, dd, J 7.4 & 16 Hz, vinylH), 7.33 (1 H, d, J 16 Hz, vinylH), 7.33 (2 H, m, ArH), 7.63 (1 H, m, ArH), and 9.72 (1 H, d, J7.6 Hz, CHO); m/z [CI(NH3)] 306, 308, 310 (MNH4+), and 288, 290, 292 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([NH:8][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cc(Cl)cnc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc(Cl)cnc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
5.16 g (24.8 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine, 7.09 g (52.1 mmol) of p-anisaldehyde and 13.1 g (62.0 mmol) of sodium triacetoxyborohydride were dissolved in 100 mL of DCM and stirred at r.t. overnight. The next day DCM was replaced with chloroform, 5 g excess of sodium triacetoxyborohydride and 3 g excess of p-anisaldehyde were added and the reaction was conducted at 65° C. for 3 h. The mixture was worked up with aqueous sodium bicarbonate and purified on silica followed by recrystallization from ethyl acetate/hexanes mixture to give 3.40 g (42%) of the product as a white solid. MS (M+H)/z=328.9
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CN(C)C=O>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: OCC(O)CCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(O)CO
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
83 g (0.5 mol) of 3-methylxanthine are dissolved in 1250 ml of dimethylformamide, and 12 g (0.5 mol) of sodium hydride are added in portions at room temperature, while stirring. Stirring is continued for 30 minutes, after which 55.3 g (0.5 mol) of 1-chloro-2,3-propanediol in 100 ml of dimethylformamide are added dropwise and the mixture is heated for 18 hours at 110° C., while stirring. Working up is carried out as described in Example 55a).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35][CH3:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31]COC)(=[O:11])=[O:10])[CH:8]=1)#[N:2].Cl>C(O)(C)C.O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35][CH3:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:17][C:16]=2[OH:31])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: COCOc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(-c2ccccc2S(C)(=O)=O)cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a suspension of 14.89 g of 5-cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide in a mixture of 30 mL of isopropanol and 90 mL of tetrahydrofuran was added 11.7 mL of concentrated hydrochloric acid. After being stirred at 50° C. for 2 hours, the reaction mixture was diluted with 50 mL of water, and extracted with 150 mL of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate-methanol) to give 10.22 g of 5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide as a colorless amorphous material.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH3:18][O:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[N:10][CH:11]=1
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(O)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 0.1 %

Procedure:
To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H2 (15 psi), stirred at RT for 45 min, filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. MS (ESI) m/z 156.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18].[CH2:28](OC1OC(C(O)=O)=CC=1)[CH2:29]CCCCCCCCCCCC.C([Mg]Br)C.C[Mg]Br>>[CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([CH2:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Agent: CC[Mg]Br
Agent: C[Mg]Br
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)CC)o1

Procedure:
When in the procedure of Example 1 (B) an appropriate amount of 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)-2-furoic acid, and an appropriate amount of ethyl magnesium bromide is substituted for methyl magnesium bromide, ethyl 5-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone is obtained.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21](Cl)=[O:22])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].O>[Na]>[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[O:22])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)Cl)s1
Agent: [Na]
Solvent: O
Product: C[C@@H]1CN(C(=O)C2CC2c2ccc(C(C)(C)C)s2)C[C@H](C)O1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
cis-2,6-Dimethylmorpholine (6.6 g, 0.057 mol) was added dropwise to a solution of 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (2.50 g, 0.01 mol) in sodium dried ether (20 ml) at 10° C. and after complete addition the solution was stirred at 20° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether (2×75 ml). The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl-2,6-cis-dimethylmorpholine as a yellow oil. This oil was separated by column chromatography (silica eluted with petroleum ether/ethyl acetate 1:1) to give 2-(5-t-butylthiophen-2-yl)-trans-cyclopropanecarbonyl)-2,6-cis-dimethylmorpholine (1.70 g, 53%) and 2-(5-t-butylthiophen-2-yl)-cis-cyclopropanecarbonyl)-2,6-cis-dimethylmorpholine (0.94 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=c1cc(NC2CCCCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1,4-dioxane (3 mL), cyclohexanamine (48.5 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), and Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-(cyclohexylamino)quinolin-2(1H)-one as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([N:6]2[C:10]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=3[OH:21])=[CH:9][CH:8]=[N:7]2)[CH2:3]1.CC(C)([O-])C.[K+].[S:28]1[CH:32]=[C:31]([N:33]([S:41]([C:44]2[CH:49]=[C:48]([F:50])[C:47](F)=[CH:46][C:45]=2[F:52])(=[O:43])=[O:42])C(=O)OC(C)(C)C)[N:30]=[CH:29]1.O>C(#N)C>[F:52][C:45]1[CH:46]=[C:47]([O:21][C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[C:10]2[N:6]([CH:4]3[CH2:3][N:2]([CH3:1])[CH2:5]3)[N:7]=[CH:8][CH:9]=2)[C:48]([F:50])=[CH:49][C:44]=1[S:41]([NH:33][C:31]1[N:30]=[CH:29][S:28][CH:32]=1)(=[O:43])=[O:42]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2F)C1
Reaction time: 0.5 h

Procedure:
2-[1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenol, (Preparation 855, 137 mg, 0.00046 mol) was dissolved in acetonitrile (10 mL) and treated with potassium tert-butoxide (57 mg, 0.0005 mol) and stirred under nitrogen for 30 minutes. Tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation 297, 182 mg, 0.00046 mol) was added and the solution stirred for 2 hours. Water (0.2 mL) was added and the solution evaporated. The residue was suspended in water and extracted with ethyl acetate (1×20 mL). The organic layer was separated and washed with brine (2×20 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give a foam. The foam was purified using an ISCO™ Companion (4 g. silica gel, eluting with dichloromethane:acetic acid 99.5:0.5 to dichloromethane:methanol:acetic acid 95:5:0.5). The appropriate fractions were evaporated to give a film. The film was triturated with diethyl ether to give the title compound as a white solid (11 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]([O-])=[O:21].[Na+]>C(O)(=O)C.C(O)C.O>[CH2:1]([N:8]1[C:15]([NH2:16])=[C:14]([N:20]=[O:21])[C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 1-benzyl-3-propyl-6-amino-uracil (6.2 mmol) in 80% acetic acid (15 mL) and 30 mL of ethanol, was stirred at 40° C. while a solution of NaNO2 (9.3 mmol) in water (10 mL) was added drop wise. The reaction was stirred for 30 minutes at 40° C. and after concentration the product precipitated from the reaction mixture and was collected by filtration. (Pink solid. Yield 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.N1CCCC1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.C(Cl)Cl.O>CO.CC#N>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: Clc1ccc(CBr)cc1Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(=O)CC2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
15 g (85 mmol) of 7-methoxy-3,4-dihydronaphthalen-2(1H)-one were dissolved in 200 ml of dry MeOH under nitrogen. Then 6.66 g (94 mmol) of pyrrolidine were added dropwise and slowly and the colour changes. The mixture is stirred for one h. The solvent was reduced under vacuo and the residue was dissolved in MeCN. At 5° C. 22.5 g (94 mmol) 4-(bromomethyl)-1,2-dichlorobenzene dissolved in MeCN were added and the mixture was stirred over night at RT. The solvent was reduced under vacuo and the residue was mixed with MeOH/CH2Cl2/H2O 1:1:1 (50 ml, 50 ml, 50 ml) and 10 ml of glacial acid were added. The mixture was stirred over night. Work-up: The reaction mixture was put on ice water and extracted 3× with CH2Cl2. The combined organic layers were washed 1× with NaHCO3 solution and 1× with saturated NaCl solution. The organic phase was dried on MgSO4 and the solvent was evaporated. The residue (31.5 g) was purified by flash-chromatography on silica gel with heptane/EtOAc 2:1. 24.1 g (71.7 mmol, 84%) of the product were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH:2]=1
Reactant: CCO
Reactant: O=C(O)CCc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cnc2ccccc2c1

Procedure:
A solution 3-(3-quinolinyl)propanoic acid (4.4 g) and concentrated sulphuric acid (2 ml) in absolute ethanol (50 ml) was refluxed for 5 h. then, evaporated to dryness. Aqueous sodium bicarbonate (8%, 50 ml) was added, the mixture extracted with ether (2×100 ml) and the ethereal extracts dried (Na2SO4). Evaporation of the ether and distillation of the residual oil (150°/0.06 mm) gave the title compound (4.3 g).
Reaction SMILES: [N:1]([CH:4]([CH3:20])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([CH2:16][CH:15]=1)=[C:9]1[C:10]([N:6]([CH2:5][CH:4]([NH2:1])[CH3:20])[N:7]=[CH:8]1)=[CH:11]2
Reactant: COC1=CCC2=c3cnn(CC(C)N=[N+]=[N-])c3=CC2=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: COC1=CCC2=c3cnn(CC(C)N)c3=CC2=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
1.58 g (5.86 mmol) of (RS)-1-(2-azido-propyl)-6-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 680 mg (5.86 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.81 g (86%) of (RS)-2-(6-methoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 192°-194° were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:6][S:7][C:8](=[O:10])[CH3:9])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:6][S:7][C:8](=[O:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CSC(C)=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)c1ccc(N)cc1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 2-(4-(benzyloxycarbonylamino)phenyl)-3-(acetylthio)-propanoic acid ethyl ester (0.2 g, 0.54 mmol) in 5 mL of methylene chloride was added 5 mL of trifluoroacetic acid. After 0.5 hours, the reaction mixture was concentrated in vacuo. The compound was purified by flash chromatography through silica gel (1/1 hexanes/ethyl acetate) to afford 2-(4-aminophenyl)-3-(acetylthio)propanoic acid ethyl ester (0.12 g, 85%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16].C(O)(=O)C>C1COCC1>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COCCCCCC(=O)OC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCCCCC(=O)CP(=O)(OC)OC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of dimethyl methylphosphonate (8.88 g) in THF (60 ml) was cooled to -60° C. , to which n-butylithium (1.55-M, 46.2 ml) was added dropwise. After addition, the solution was stirred at -60° C. for 30 minutes. A solution of methyl 6-methoxy-caproate (5.65 g) in THF (50 ml) was added dropwise to the resulting solution and held at -60° C. overnight, and at room temperature for 2 hours. After the reaction solution was cooled to 0° C., the reaction was neutralized by addition of acetic acid (4 ml). The crude product obtained after the usual work-up was chromatographed (dichloromethane/methanol (5%)).