Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.C1COCC1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cc(C)nc(S)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(SCc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To 4,6-dimethylpyrimidine-2-thiol (9.1 g) was added THF (70 ml), and to this solution was added triethylamine (21.5 ml) and then, 4-nitrobenzyl bromide (10 g), and the mixture was stirred for 5 hours at 50° C. After cooling to room temperature, the mixture was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4,6-dimethyl-2-[(4-nitrobenzyl)sulfanyl]pyrimidine (7.2 g).
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=[N+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O-:6]
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1cc([N+](=O)[O-])ccc1O
Yield: 75.1 %

Procedure:
A mixture of tert-butylhyroxylamine (10.5 g, 120 mmol), 2-hydroxy-5-nitrobenzaldehyde (15 g, 90 mmol) and p-toluenesulfonic acid (1.6 g, 9 mmol) in benzene (375 mL) was refluxed in a flask fitted with a Dean-Stark trap until no more aldehyde was detectable by TLC. The mixture was cooled and the resulting suspension was filtered. The title compound was isolated in 75.1% yield as a pale yellow solid, m.p. 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][CH:33]1[CH2:38][NH:37][CH2:36][CH:35]([CH3:39])[N:34]1[C:40](=[O:44])[CH2:41][O:42][CH3:43]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][C@H:33]([CH3:32])[N:34]([C:40](=[O:44])[CH2:41][O:42][CH3:43])[C@H:35]([CH3:39])[CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCC(=O)N1C(C)CNCC1C
Product: COCC(=O)N1[C@H](C)CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1C

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-cis-3,5-dimethyl-piperazin-1-yl]-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2,6-dimethyl-piperazin-1-yl)-2-methoxy-ethanone following General Procedure C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(OC2C=CC(O)=CC=2)=CC=1.[H-].[Na+].[C:45]([O:49][C:50](N1CCC[C@H]1COS(C1C=CC(C)=CC=1)(=O)=O)=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C>[C:50]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:51]
Reactant: FC(F)(F)c1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-[4-(4-trifluoromethyl-phenoxy)-phenoxymethyl]-pyrrolidine To a solution of 4-(4-trifluoromethyl-phenoxy)-phenol (1.25 g, 5.0 mmol) in DMF (13 mL) was added 60% NaH (5.0 mmol) at 0° C. and the resulting mixture was stirred at rt for one hour. This was followed by addition of (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.78 g, 5.0 mmol) in one portion to above reaction and the reaction was heated at 60° C. for 16 h. The mixture was partitioned between water and diethyl ether. The organic layer was washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo to obtain an oil as (S)—N-Boc-2-[4-(4-trifluoromethyl-phenoxy)-phenoxymethyl]-pyrrolidine, which was dissolved in 20 ml of DCM and treated with trifluoroacetic acid (5 mL) at if for one hour. The reaction was evaporated in vacuo to give a tan oil. Water was added and pH was adjusted to 10 with aqueous saturated Na2CO3 solution. The aqueous phase was extracted with EtOAc and the organic layer was washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo to obtain an oil, which was purified by flash chromatography eluting with 2-5% hexane/EtOAc to afford the title compound (1.45 g, 86%) as a light tan solid: MS; m/z 338 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=O)[N:14]([CH3:17])[C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:11]([CH2:13][N:14]([CH3:17])[CH2:15]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)C2CN(Cc3ccccc3)CC2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC2CN(Cc3ccccc3)CC2C1

Procedure:
A solution of 5-benzyl-2-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione (3.6 g) in THF (15 ml) was added dropwise to a suspension of lithium aluminum hydride (1.68 g) in THF (20 ml) while cooling in ice. The mixture was heated to reflux for 4 hours and then, at 0° C., water (1.8 ml), sodium hydroxide solution (10 M; 1.8 ml) and water (2.5 ml) were cautiously added. The precipitate was filtered off with suction and washed with ethyl acetate. The filtrate was concentrated. The product with the molecular weight of 216.33 (C14H20N2); MS (ESI): 217 (M+H+) was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1I.[I:12]C1C=C(C=C([N+]([O-])=O)C=1)N>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[C:6]([I:12])[CH:7]=1
Reactant: Nc1cc(I)cc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(F)c1I
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Fluoro-3-nitroiodobenzene To a 25 mL round-bottom flask equivuipped with a magnetic stir bar 3-iodo-5-nitroaniline (543.3 mg, 2.06 mmol) and methylene chloride (10 mL) were added under nitrogen. Nitrogen was bubbled through the colorless solution for 15 min. The solution was cooled to 0° C. in an ice bath. At that point approximately 500 mg nitrosonium tetrafluoroborate was added in one portion making a cloudy precipitate. The reaction was allowed to continue stirring for 2 hours. The mixture was kept under nitrogen as 10 mL dry, deoxygenated ortho-dichlorobenzene was added. A distillation apparatus was fitted to the reaction flask. The flask was placed in an oil bath and was heated until the material had completely distilled over. The crude product was isolated by washing the residue through a short column (74 mL silica, hexane). Purification by silica gel chromatography (74 mL silica, hexane) afforded 279.4 mg (50%) of 5-fluoro-3-nitroiodobenzene. Data for 5-fluoro-3-nitroiodobenzene: 1H NMR (400 MHz, acetone-d6) 8.36 (s, 1 H), 8.00 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=O)[O:19]C1C=CC=CC=1>CN(C)P(=O)(N(C)C)N(C)C>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18]([CH:9]1[C:8](=[O:10])[S:7][C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]1=2)=[O:19]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: O=C1Cc2ccc(Cl)cc2S1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1nccs1)C1C(=O)Sc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
De-oiled sodium hydride, obtained by de-oiling 0.82 g of a 50% suspension in mineral oil, was added at 10° to a solution of 3 g of 6-chloro-2,3-dihydro-2-oxo-benzo[b]thiophen and 3.85 g of phenyl N-(2-thiazolyl)-carbamate in 30 ml of hexamethylphosphoric acid triamide. After a few minutes, the cooling bath is removed and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is poured into a mixture of 1 liter of ice-water and 20 ml of concentrated hydrochloric acid, the precipitate is filtered off with suction and washed successively with ice-water, diethyl ether and hexane and taken up in 50 ml of acetone, the acetone solution is heated under reflux, allowed to cool, diluted with 100 ml of diethyl ether and cooled for some time in an ice bath and the precipitate is again filtered off with suction. N-(2-Thiazolyl)-6-chloro-2-oxo-2,3-dihydro-benzo[b]thiophen-3-carboxamide with a melting point of 276°-289° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[N:24][CH:25]=1>>[F:29][CH:27]([F:28])[O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])=[CH:21][CH:22]=1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: FC(F)Oc1ccc(CBr)cn1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)nc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 5-(bromomethyl)-2-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.82 min.; [M+H]+: 393.28 g/mol.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]3[N:18]=[CH:19][NH:20][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:22]1([C:28]([O:30][CH3:31])=[O:29])[C:26](=[O:27])[CH:25]=[CH:24][S:23]1>C(Cl)(Cl)Cl>[OH:27][C:26]1[CH:25]=[C:24]([N:20]2[C:14]3[CH:13]=[C:12]([C:10](=[O:11])[NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:17]=[CH:16][C:15]=3[N:18]=[CH:19]2)[S:23][C:22]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: O=C(NCCN1CCOCC1)c1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.27 g of 1H-imidazo[4,5-c]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide in 150 ml chloroform was slowly added a solution of 1.27 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 100 ml chloroform and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was washed with water (3×50 ml) and the organic layer was dried with MgSO4 and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by flash chromatography (dichloromethane/methanol, elution gradient 10/0 to 9/1 (v/v))) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([N:18]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([N:18]([CH2:27][C:28]([OH:30])=[O:29])[C:19]3[CH:20]=[C:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[CH:24]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)cc(N(CC(=O)OC(C)(C)C)C(=O)c2cccnc2SCc2ccnc(N)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(CC(=O)O)C(=O)c2cccnc2SCc2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(tert-butoxycarbonylmethyl)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound No. 7-1, 40 mg, 0.084 mmol) was dissolved in ethyl acetate (1.0 mL), and 4 N hydrochloric acid in ethyl acetate (1.0 mL) was added thereto, and then the mixture was stirred for 18 hours at room temperature. The precipitated solid was filtered off with diethyl ether and dried under reduced pressure to give 30 mg of the target compound as a colorless solid. (Yield 86%)
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][CH2:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:20]([NH2:23])[C:21]#[CH:22]>C(O)C>[CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[N:23][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C1CCC2CC1CC(=O)N2Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1CC2CC(Cc3cccnc32)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A flask charged with a stir bar, 2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (for preparation see J. Chem. Soc., Perkin Trans. 1, 1999, 1157-1162; 0.80 g), NaAuCl4.2 H2O (30 mg), propargylamine (0.45 mL), and ethanol (5 mL) is heated at 100° C. with microwave irradiation for 10 min. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate/methanol 6:4:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:13](O)=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1.CN(C=O)C.Cl>ClCCl>[CH2:16]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:14])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccccc1CCc1ccccc1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
Oxalyl chloride (9.1 ml) was added to a suspension of 2-bibenzylcarboxylic acid (2-phenethylbenzoic acid) (20 g) in dichloromethane (200 ml) followed by 0.1 ml of DMF. The mixture was stirred for 15 hours and evaporated to dryness. The residue was dissolved in diglyme (150 ml) and cooled to -70° C. under argon. Lithium tri-t-butoxyaluminohydride (177 ml of a 0.5M solution in diglyme) was added dropwise such that the temperature of the reaction mixture did not exceed -65° C. The reaction mixture was stirred for a further 2 hours at -70° C. and then poured onto ice. The slurry obtained was acidified (HCl) and extracted with diethyl ether (3×75 ml). The combined ether extracts were washed with brine and dried (MgSO4). The solvent was removed and the residue dissolved in petroleum ether (BP 60-80° C.) and washed once with aqueous saturated sodium bicarbonate, five times with water and twice with brine then dried. Removal of the solvent gave an oil which was purified by chromatography on silica, eluting with dichloromethane-hexane (1:1 v/v), to give 2-(phenethyl)benzaldehyde. (4.83 g).
Reaction SMILES: C(O[CH:4]=[N:5][C:6]#[N:7])C.[NH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][S:11][C:10]1([CH3:20])[CH3:19]>C(O)C>[C:6]([NH:5][CH:4]=[N:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][S:11][C:10]1([CH3:20])[CH3:19])#[N:7]
Reactant: CCOC=NC#N
Reactant: CC1(C)SCc2ccccc2C1N
Solvent: CCO
Product: CC1(C)SCc2ccccc2C1N=CNC#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
10.0 g of N-cyanoimidoformic acid ethyl ester are added dropwise to 16.7 g of 4-amino-3,3-dimethylisothiochroman in 10 ml of dry ethanol. The exothermic reaction is complete after 2 hours. The mixture is cooled to 0° C., and the precipitate is filtered off and washed with a small amount of ethanol. After drying, 14.3 g of N-cyano-N'-(3,3-dimethylisothiochroman-4-yl)-formamidine are obtained in the form of colourless crystals having a melting point of 164°-166° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[C:32]([CH2:40][CH3:41])[C:31]4=[O:42])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[C:32]([CH2:40][CH3:41])[C:31]4=[O:42])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCOc1c(CN2CCC(n3ccc(C(=O)OC)c(CC)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(CN2CCC(n3ccc(C(=O)O)c(CC)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.73 mL) was added to a methanol (3 mL) solution of methyl 1-(1-((6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (382 mg), and the mixture was stirred at 50 C for 1 hour. The reaction mixture was cooled to room temperature and neutralized with 2 M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from water, and the obtained solid was recrystallized (ethanol/diisopropyl ether/hexane) to obtain the title compound (211 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:1]([NH:8][C@H:9]([C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1CCNC1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1

Procedure:
2.50 g (10 mmol) BOC-methionine was coupled to 1.72 ml (20.6 mmol) pyrrolidine according to procedure B. Yield of crude product 3.38 g. The product was purified with a silica column using ethyl acetate as eluent. Yield 2.81 g (9.3 mmol, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[S:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:27]2[CH:28]=[C:29]([CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[S:30][CH:31]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2csc(CN3CCOCC3)c2)OC1(C)C
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3csc(CN4CCOCC4)c3)cnc2N)ccn1

Procedure:
Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-morpholine gives the compound “A15”;
Reaction SMILES: CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@@H](C/C=C/C)C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C[CH:81]([CH3:83])C)N(C)C(=O)CN(C)C1=O.FC(F)(F)S([O:91][Si:92]([CH2:97][CH3:98])([CH2:95][CH3:96])[CH2:93][CH3:94])(=O)=O.O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:93]([Si:92]([O:91][Si:92]([CH2:81][CH3:83])([CH2:95][CH3:96])[CH2:93][CH3:94])([CH2:97][CH3:98])[CH2:95][CH3:96])[CH3:94]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC[Si](CC)(CC)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclosporin A (3.606 g, 3 mmol) was dissolved in dry pyridine (8 mL) and then DMAP (122 mg, 1 mmol) was added. The reaction mixture was cooled to 0° C. and then triethylsilyl trifluoromethanesulfonate (3.6 mmol) added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured slowly into water with stirring. The precipitated triethylsilyl ether was filtered off and washed with water. The collected cake was dissolved in a minimum volume of methanol and added to a 5% citric acid solution and stirred for 30 minutes. The precipitated product was collected by filtration and washed with water until the pH of the filtrate reached that of the water. The solid triethylsilyl ether was dried at 50° C. under vacuum to give a colorless solid. Triisopropylsilyl and tert-butyldimethylsilyl protecting groups were also introduced by following an analogous procedure.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]([NH2:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9].CN(C1CCCCC1)C>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[C:8]([NH:16][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: C1CCC2OC2C1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CN(C)C1CCCCC1
Product: CC(C)(C)CC(C)(C)NC1CCCCC1O

Procedure:
In a 1000 cc three neck flask was charged 86.6 gms (0.88 moles) of cyclohexene oxide, 114.0 gms (0.88 moles) of t-octyl amine, 5 grams of zinc chloride, and 2.2 gms of polycat-8 (Abbot Laboratories). The mixture was then heated at 95°-100° C. for about 10 hours. The crude mixture was stripped of low boilers and then was dissolved in methylene chloride and washed with ammonium hydroxide solution. The methylene chloride solution was dried over magnesium sulfate, filtered and stripped to give a liquid. The product was distilled at 121° C. (0.3 mmHg) to give a colorless liquid. A GLC analysis of the distilled product showed it to be 98.6% purity.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCCCC1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: Nc1ncnn2c(-c3cccc(CNC4CCCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 11 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclohexanone as starting materials, 40 mg (11%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (m, 2 H), 3.60 (t, 1 H), 1.90 (m, 4 H), 1.70 (m, 2 H), 1.10 (m, 4 H); ES-MS m/z 528.18 [M+H]+, HPLC RT (min) 2.51.