Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C=O.[SH:15][CH2:16][C:17]([OH:19])=O.[C:20]1(C)C(C)=CC=CC=1>O>[O:19]=[C:17]1[CH2:16][S:15][CH2:20][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)CS
Reactant: Cc1ccccc1C
Agent: C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CSCC2=O)cc1

Procedure:
Ethyl p-aminobenzoate (7.3 g) was reacted with 37% formalin (formaldehyde in water) (3.2 ml), mercaptoacetic acid (3.0 ml) and xylene (300 ml). This reaction mixture was refluxed and the water formed thereby was removed azeotropically. After all the water was removed, xylene was evaporated under reduced pressure and the residual oil taken up in methylene chloride. Removal of the methylene chloride solvent left an orange solid which was recrystallized from ethanol to give ethyl 4-(4-oxo-3-thiazolidinyl)benzoate. This product had a melting point of 68°-69° C.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[O:18]=[C:17]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:16]1
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared according to the method described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90. To an ice cooled solution of N-(phenylmethyl)-D-serine (8.90 g, 45.59 mmol) in 2N NaOH solution (50 mL) was added chloroacetyl chloride (4.36 mL, 54.71 mmol), dropwise over 15 minutes. The reaction was stirred for 30 minutes before adding 30% NaOH solution (4.5 g in 15 mL) and stirring at R.T. for 2 and ½ hours. It was cooled in an ice bath before adding c.HCl solution to pH<1. solid precipitated out. Filtered. Suspended in isopropanol and heated at reflux for 10 minutes. Filtered hot. Solvent evaporated to afford a pale yellow solid. Triturated with Et2O to afford the title compound as a cream solid in 29% yield.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.14 ml (10.5 mmol) of phenyl isocyanate are slowly added dropwise to a solution of 1.90 g (10.0 mmol) of 4-amino-1-benzylpiperidine and 1.46 ml (10.5 mmol) of triethylamine in 40 ml of dichloromethane. The reaction mixture may subsequently be stirred at room temperature for 1 h, and is then evaporated to dryness in vacuo. The residue is mixed with 50 ml of diethyl ether, stirred well, separated off by filtration, washed with 5 ml of diethyl ether and dried in a high vacuum. 2.62 g (85%) of the title compound are obtained as colourless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29]>C1COCC1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].O>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Sodium hydride (48 mg, 60% dispersion in mineral oil, 12.0 mmol) was added to a cooled (0° C.) mixture of 1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.56 g, 1.16 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (0.25 g, 1.20 mmol) in dry THF (3.5 mL). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then diluted with DCM (40 mL), saturated aqueous sodium carbonate solution (20 mL) and water (20 mL). The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash column chromatography (silica, 5 g cartridge, Si-SPE, DCM) to afford the title compound as a beige solid (0.59 g, 80%). LCMS (Method B): RT=4.28 min, M+H+=617/619.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[C:18]([O:28][CH3:29])[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([O:28][CH3:29])[N:17]=1
Reactant: COc1cc(N2CCNCC2)nc(OC)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)nc(OC)n1
Yield: 111.1 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2,6-dimethoxypyrimidin-4-yl)piperazine (1.1 g) and potassium carbonate (1.0 g) in dimethylformamide (10 ml) was stirred at 80° C. for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.1 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) and crystallized from ethyl acetate:diisopropyl ether (1:2, 30 ml) to give the title compound (1.0 g) as white crystals, m.p.=89-90° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@H:20]2[C@@H:24]3[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@@H:23]3[C@@H:22]([C:30](O)=[O:31])[O:21]2)=[C:13]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:12]=1.C(Cl)(=O)C(C)(C)C.[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH2:52])=[O:50]>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH:52][C:30]([C@@H:22]1[C@@H:23]2[C@@H:24]([O:25][C:26]([CH3:28])([CH3:29])[O:27]2)[C@H:20]([N:17]2[CH:16]=[N:15][C:14]3[C:18]2=[N:19][C:11]([Cl:10])=[N:12][C:13]=3[NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[O:21]1)=[O:31])=[O:50]
Reactant: CC(C)(C)C(=O)NN
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NNC(=O)C(C)(C)C)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Diisopropylethylamine (0.487 ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (350 mg) in dry tetrahydrofuran (8 ml) at 0° C. under nitrogen. After 5 min pivaloyl chloride (0.098 ml) was added and the mixture was stirred at 0° C. for 2.5 h. 2,2-Dimethyl-propionic acid hydrazide was added in tetrahydrofuran (2 ml) at 0°, and stirring was continued at 0-22° C. overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (2×30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was azeotroped with dichloromethane (10 ml) to give the title compound as a cream solid (357 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH2:37]>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NCCc1ccccn1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCc3ccccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(pyridin-2-yl)ethanamine were reacted to give 322. [M+H]+ 484.6.
Reaction SMILES: [CH:1]1[C:14]2[CH:13](O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]([Cu])#[N:21].C1C2CC3C(=CC=CC=3)SC=2C=CC=1.C1C2C(=O)C3C(=CC=CC=3)SC=2C=CC=1>CCOCC.C1C=CC=CC=1>[CH:1]1[C:14]2[CH:13]([C:20]#[N:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#C[Cu]
Reactant: OC1c2ccccc2Sc2ccccc21
Agent: O=c1c2ccccc2sc2ccccc12
Agent: c1ccc2c(c1)Cc1ccccc1S2
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: N#CC1c2ccccc2Sc2ccccc21
Temperature: 2.5 °C
Yield: 58.3 %

Procedure:
A suspension of 9H-Thioxanthen-9-ol [32] (2.14 g, 9.98 mmol) in anhydrous Et2O (20 mL) under N2 and SOCl2 (0.8 mL, 11.48 mmol) was added with caution via syringe with stirring at 0-5° C. The alcohol dissolved before a white solid began to separate. After stirring (1 hr.) at room temperature, the solvent was removed under reduced pressure and C6H6 (10 mL) was added and solvent removed to dryness again. All manipulations were performed with rigorous exclusion of air. Anhydrous C6H6 (20 mL) and CuCN powder (1.79 g, 19.97 mmol) were added and the suspension was stirred at reflux (4 hr.).The reaction mixture was filtered while hot and the residue was washed with hot C6H6 (50 mL). The filterate was evaporated to give a crystalline residue containing thioxanthene and thioxanthen-9-one as well as the desired nitrile. One recrystallizations from hexane removed thioxanthene and one recrystallizations from 2-propanol removed most of the thioxanthen-9one to provide 1.3 g (59%) of the pure nitrile, mp. 97-98° C.
Reaction SMILES: C(OC(N1C2C(=CC=C([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[O:33][CH3:34])=[CH:21][CH:20]=3)C=2)C=C1)=O)(C)(C)C.[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[C:46](CO)[CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].FC1C(F)=CC(C2C=CC(O)=CC=2)=C(OC)C=1>>[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[C:46]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[O:33][CH3:34])=[CH:21][CH:20]=3)[CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21
Agent: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)OC(C)(C)C)cc1

Procedure:
4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester was synthesized by a procedure similar to 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester from starting materials 4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester and 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol to yield the product as a white solid (880 mg, 70%). LC-MS (ES) calculated for C27H25F2NO2, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[C:17]([O:21][C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:26]3[CH2:27][CH2:28][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]3)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COC(=O)C1(c2ccc(C(=O)Cl)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(C(=O)N3CCC(NC(=O)OC(C)(C)C)C3)cc2)CC1
Temperature: 50 °C
Yield: 86.3 %

Procedure:
Part A. 1-(4-Chlorocarbonyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.78 g, 3.28 mmol), pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.60 g, 3.22 mmol) and DIEA (1.18 mL, 6.44 mmol) were stirred in CH2Cl2 (10 mL) at rt under N2 overnight. H2O was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, dried in vacuo. The residue was dissolved in MeOH (20 mL) and 1N NaOH (10 mL) was added. The reaction was heated at 50° C. for 2.5 h. The solvents were evaporated. The residue was extracted with Et2O, the H2O layer was acidified with citric acid, and extracted with Et2O (2×), washed with brine, dried over MgSO4, filtered, and concentrated to dryness to yield 1-[4-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-phenyl]-cyclopropanecarboxylic acid methyl ester (1.08 g, yield: 83.0%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl.Cl.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]2[NH:47][C:46](=[O:48])[O:45][N:44]=2)[CH:40]=[CH:41][CH:42]=1.CCN(C(C)C)C(C)C>CC#N>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]4[NH:47][C:46](=[O:48])[O:45][N:44]=4)[CH:38]=3)=[O:16])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: Nc1cccc(-c2noc(=O)[nH]2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2noc(=O)[nH]2)c1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A 2L three-necked-reaction flask was charged with [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid (100 g, 243 mmol) and MeCN (600 mL). At room temperature SOCl2 (19.5 mL, 267.3 mmol) was added via addition funnel. In a 3L three-necked-flask a slurry of 3-(3-amino-phenyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride salt (53.47 g, 250.3 mmol) in MeCN (300 mL) was treated with DIPEA (148 mL, 851 mmol) at room temperature, then cooled to −10° C. The solution of the acid chloride was then added to the amine solution to maintain the temperature below −5° C. Upon consumption of starting material (30 minutes) the reaction mixture was quenched by addition of 1N HCl (650 mL) followed by addition of water (300 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting suspension was then cooled in an ice bath (1 h) and the solid collected by vacuum filtration and washed with MeCN (50 mL) to yield the title compound as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][OH:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:21][CH2:22][CH:23]=[CH2:24])[CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=CCNC(CCO)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNC(CCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(1-allylamino-3-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (0.264 g, 0.794 mmol) in DCM (15 mL) cooled at 0° C. was added successively methanesulfonyl chloride (68 μL, 0.873 mmol) and Et3N (0.133 mL, 0.953 mmol). The mixture was stirred at RT for 1.5 h, and then diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method B): RT 2.14 min [M+H]+ 411.
Reaction SMILES: C(OC(N1CCC(NCC2C=CN3C=2C(NC2C=C4C(=CC=2)N(CC2C=CC=C(F)C=2)N=C4)=NC=N3)CC1)=O)(C)(C)C.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([N:56]([CH2:58][C:59]2[CH:60]=[CH:61][N:62]3[C:67]=2[C:66]([NH:68][C:69]2[CH:70]=[C:71]4[C:75](=[CH:76][CH:77]=2)[N:74]([CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([F:85])[CH:80]=2)[N:73]=[CH:72]4)=[N:65][CH:64]=[N:63]3)[CH3:57])[CH2:52][CH2:51]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:85][C:81]1[CH:80]=[C:79]([CH:84]=[CH:83][CH:82]=1)[CH2:78][N:74]1[C:75]2[C:71](=[CH:70][C:69]([NH:68][C:66]3[C:67]4=[C:59]([CH2:58][N:56]([CH3:57])[CH:53]5[CH2:52][CH2:51][NH:50][CH2:55][CH2:54]5)[CH:60]=[CH:61][N:62]4[N:63]=[CH:64][N:65]=3)=[CH:77][CH:76]=2)[CH:72]=[N:73]1
Reactant: CN(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(NCc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C1CCNCC1
Yield: 37 %

Procedure:
Similarly, 4-({4-[1-(3-fluoro-benzyl)-1H-indazol-5ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-amino)-piperidin-1-carboxylic acid tert-butyl ester was convertet to 4-({4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-methylamino)-piperidin-1-carboxylic acid tert-butyl ester which was treated with TFA at 0° C. for 1 h to give the title compound as a solid (overall yield 37%). MS: 485 (M+H)+; HPLC Ret Time: 0.95 min (YMC 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[C:15](OC(=O)C)(=O)C.C(Cl)(=O)C>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COC(=O)CCc1ccccc1C(=O)O

Procedure:
2-carboxybenzenepropanoic acid (9.7 g., 0.05 mole), acetic anhydride (15.5 g., 0.15 mole) and acetyl chloride (0.5 g) in dichloromethane (200 ml) was boiled at reflux under nitrogen for 16 hr. The solvents were removed at high vacuum and the residual cyclic anhydride was heated at reflux with methanol (250 ml) for 2 hrs. Evaporation of solvent gave the sub-title compound as an oil which crystallised with petroleum ether (b.p. 60°-80°) to a solid (6.3 g) mp 76°-79°. This was further purified by continuous extraction of the crude product with boiling petroleum (b.p. 40°-60°) in a Soxhlet apparatus. The pure compound, mp 79°-81° separated from the extracts on cooling.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([CH:9]([C:7]#[N:8])[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: COC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml of N,N-dimethylformamide, 2.17 g (21.7 mmol) of methyl cyanoacetate with a purity of 99% and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 60° C. for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, 50ml of ethyl acetate was added to the mixture, and 2.9 ml (34.8 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 30 ml a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: toluene) to obtain 1.81 g (isolation yield: 84%) of methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate as a yellowish oily product with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[O:39][C:40](=[O:51])[CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[C:46]([CH3:50])([CH3:49])[CH:47]=O.CCOCC>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:49][C:46]([CH3:50])(/[CH:47]=[CH:18]\[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7])/[CH:45]=[CH:44]\[CH2:43][CH2:42][CH2:41][C:40]([OH:39])=[O:51]
Reactant: CCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC/C=C\C(C)(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCC/C=C\C(C)(C)/C=C\CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
A 1.4 ml. portion of n-butyllithium (1.6 M solution in hexane) was added to a solution of 1.4 g (2.74 mmol) of n-dodecyltriphenylphosphonium bromide in 5.5 ml of 2:1 tetrahydrofuran-hexamethylphosphorictriamide, at -78° C., under argon. The solution turned orange-red in color. To this solution was then added 0.350 g (1.77 mmoles) of (Z)-8-oxo-7,7-dimethyl-5-octenoic acid methyl ester dissolved in 1 ml of tetrahydrofuran, using a syringe. The reaction mixture was stirred for 30 minutes at -78° C. and an additional 45 minutes at 0° C. The product was isolated by ether extraction using the conventional workup procedure and then chromatographed on silica gel. Hexane-ether (19:1) eluted 0.600 g (97%) of (Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid methyl ester. This material was dissolved in 6 ml of methanol and treated with 0.6 ml of 5% aqueous potassium hydroxide. After stirring at room temperature for 17 hours, 3 ml of the methanol was evaporated in vacuo. The remaining solution was acidified with oxalic acid and the product was extracted with ether. The ether extracts were washed with brine, dried over MgSO4 and the solvent evaporated at reduced pressure. Purification of the crude acid on a silica gel column provided 0.292 g (50.7%) of (Z,Z)-7,7-dimethyl-5,8-eicosadienoic acid (ca. 100% pure by GC analysis).