Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:14]=[C:13](Br)[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[CH:14]=[CH:13][N:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(cc(Br)n2-c2ccccc2)c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(ccn2-c2ccccc2)c1O
Yield: 82.9 %

Procedure:
A mixture of 2-bromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (34 mg, 0.094 mmol), 10% palladium on carbon (10 mg), ammonium formate (119 mg, 1.88 mmol) in EtOAc (2 ml) was refluxed overnight; then the mixture was diluted with EtOAc, the solids were filtered off, the filtrate was concentrated and the resulting residue was purified on column to give the title product (22 mg) as a clear oil; ESI MS (m/z): 283 (M+H+).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1>CN(C=O)C>[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccn[nH]2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 7.1 %

Procedure:
DIEA (0.011 mL, 0.062 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.062 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2H-pyrazol-3-yl)-phenylamine (0.009 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.0014 g of product in 7% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[NH:20][C:19]2[CH:21]=[CH:22][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Temperature: 185 °C
Yield: 43.4 %

Procedure:
Finely powdered anhydrous aluminium chloride (0.83 g, 6 mmol) was added to a stirred mixture of 4-chlorobenzonitrile (0.6875 g, 5 mmol) and 4-methylthioaniline (0.695 g, 5 mmol) over a period of 30 min. The reaction mixture was heated at 180-190° C. for 3 hours with stirring and allowed to cool to 50° C. The resultant mixture was triturated with ethyl acetate and basified with sodium hydroxide (20%) solution. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was purified by column chromatography to yield the title compound (0.6 g, 43.4%, purity 98.8% by HPLC), mp 148-150° C. 1H-NMR (CDCl3):δ 2.48 (s, 3H), 6.90-6.97(m, 2H), 7.11-7.41(m, 4H), 7.74 (bs, 2H). MS m/z:277.0 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:4].S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[Cl:22][CH2:17][C:16](=[O:18])[C:8](=[N:7][O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:9]([OH:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CON=C(C(C)=O)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: COC(=O)CON=C(C(=O)O)C(=O)CCl

Procedure:
To a solution of tert-butyl 2-methoxycarbonylmethoxyimino-3-oxobutyrate (syn isomer) (51.9 g) in glacial acetic acid (52 ml) was slowly added sulfuryl chloride (72.2 ml) at 40° C. with stirring. The reaction mixture was stirred at the same temperature for an hour. The resultant solution was concentrated under reduced pressure and the residual oil was dissolved in ethyl acetate (300 ml). The ethyl acetate layer was washed with 10% hydrochloric acid once and washed with a saturated aqueous solution of sodium chloride four times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was diluted with n-hexane (100 ml) and evaporated under reduced pressure. The white crystalline precipitates were washed with diisopropyl ether (100 ml). The precipitates were collected by filtration, dried under reduced pressure to give crystalline 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (13.4 g), mp. 127° to 128.5° C.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].S(Cl)([Cl:16])(=O)=O>ClC1C=CC=CC=1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[C:11]([Cl:16])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Solvent: Clc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F

Procedure:
The solution of 17.8 g (100 mmol) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde, 17.5 g (130 mmol) of sulphuryl chloride and 0.2 g of 2,2-azoisobutyronitrile in 50 ml of chlorobenzene was stirred at 80° C. for 6 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].N1C=CC=CC=1.[S:37](Cl)([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 76.2 %

Procedure:
To a suspension of 210 mg of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 10 ml of methylene chloride were added 0.03 ml of pyridine, 115 mg of tosyl chloride and a catalytic amount of 4-dimethylaminopyridine and the mixture was stirred at room temperature for one hour. The reaction solution was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was chromatographed over a silica gel column to afford 219 mg of the title compound.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH2:2]1.[CH3:5][NH:6][CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH3:5][N:6]([CH2:7][CH2:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:2][CH:3]([OH:1])[CH3:4]
Reactant: CC1CO1
Reactant: CNCCC(c1ccccc1)c1ccccc1
Solvent: CO
Product: CC(O)CN(C)CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
6.38 g of 1,2-epoxypropane was added to a solution of 22.5 g of N-methyl-3,3-diphenylpropylamine in 60 ml of methanol. The solution was maintained at 15°-20° C. for 3 days, and then an additional 1.16 g of 1,2-epoxypropane was added. This solution was maintained for 24 hours at room temperature. The methanol was evaporated off and the product purified by chromatography on a silica gel column (methanol gradient in chloroform), to give 24 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([CH2:6][N:7]1[C:24]2[C:23](=[O:25])[NH:22][C:21]([NH2:26])=[N:20][C:19]=2[N:9]([C@@H:10]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]2[OH:12])[C:8]1=[O:27])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:6][N:7]1[C:24]2[C:23](=[O:25])[NH:22][C:21]([NH2:26])=[N:20][C:19]=2[N:9]([C@@H:10]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]2[OH:12])[C:8]1=[O:27])([OH:3])=[O:2]
Reactant: CCOC(=O)Cn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2c(c(=O)[nH]1)n(CC(=O)O)c(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 7-carbethoxymethyl-8-oxoguanosine (1 g, 2.6 mM; Example 2), methanol (5 ml) and 1N NaOH (5 ml) was stirred at room temperature under N2 for 4 hours. Most of the methanol was removed in vacuo, and the residue was heated with water (50 ml). The solution was acidified with 1N HCl at zero degrees C to pH 5. The reaction product was purified by preparative reverse phase high performance liquid chromatography on a C-18 column (HPLC) to give the title compound as a white powder in 31 percent yield, mp above 230° C. NMR (DMSO--d6): δ10.9 (bs, 1H); 6.5 (bs, 2H) 5.6 (d, J=5Hz, 1H); 4.4 (bs, 2H). IR (KBr): 1640, 1600 and 1460 cm-1.
Reaction SMILES: C([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][CH:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CCOC(C)=O>[CH3:23][C@H:21]1[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9][NH:8][CH2:22]1
Reactant: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CNC[C@H]2Cc3ccccc3C(=O)N21
Reaction time: 72 h
Yield: 27.7 %

Procedure:
1,2,3,4,11,11a-Hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (from Isomer B, 93 mg, 0.30 mmol) and 10% palladium on carbon (40 mg) in EtOAc (9 ml) was stirred under a balloon of hydrogen. After 3 days the reaction was about 60% complete by HPLC. The catalyst was filtered off and then fresh catalyst added. After stirring an additional day under a balloon of hydrogen, the reaction was filtered through Celite® rinsing with EtOAc and methanol to afford 56 mg of crude product. Column purification (Chiralcel OD, 15% 1/1 MeOH/EtOH in hexanes) afforded pure (4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (18 mg, 28% yield). MS (ESI) 217 (M+H). Further elution afforded pure (4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (16 mg, 25% yield). MS (ESI) 217 (M+H).
Reaction SMILES: [Br-].[CH2:2]([P+:13](C1C=CC=CC=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-:32].[Na+]>CO>[C:14]1([P:13](=[O:32])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCP(=O)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A stirred mixture of undecyl-triphenyl-phosphonium bromide (45.7 g), methanol (300 ml) and 2M sodium hydroxide solution (300 ml) was heated at 50° C. for 3 hours and then concentrated under vacuum until the oily product solidified. The solid was washed with water, dried and recrystallised from petroleum spirit to give diphenyl-undecylphosphine oxide, m.p. 69° C.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][CH2:32][CH:33]([NH:40]C(=O)OC(C)(C)C)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH2:40][CH:33]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:32][NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1
Product: NC(CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using tert-butyl (2-amino-1-phenylethyl)carbamate instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 378 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.) 10.72 (1H, s) 8.67 (2H, d, J=4.10 Hz) 8.59 (1H, t, J=5.64 Hz) 8.05 (1H, d, J=6.78 Hz) 7.89 (1H, d, J=5.27 Hz) 7.40-7.50 (3H, m) 7.30 (1H, d, J=5.27 Hz) 7.26 (2H, d, J=2.68 Hz) 6.90 (1H, br. s.) 6.65 (1H, d, J=6.83 Hz) 4.40-4.55 (1H, m) 3.70-3.80 (1H, m) 3.58-3.68 (1H, m)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][CH2:17][CH:18](OS(C)(=O)=O)[CH2:19][N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22]OS(C)(=O)=O>C(O)C>[CH2:1]([N:8]1[CH2:22][CH2:21][N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH:18]1[CH2:17][F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
4.82 g (0.045 mole) of benzylamine and 9.09 g (0.09 mole) of triethylamine were added to a solution of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine [prepared as described in step (b) above] dissolved in 200 ml of ethanol. The mixture was heated under reflux for 2 hours and then concentrated by evaporation under reduced pressure. 100 ml of ethanol and 40 ml of a 2N aqueous solution of sodium hydroxide were added to the residue, and the mixture was concentrated by evaporation under reduced pressure. The residue was mixed with ethyl acetate, and insoluble materials were removed by filtration. The filtrate was freed from the solvent by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 3.60 g of 1,4-dibenzyl-2-fluoromethylpiperazine as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH2:11][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Solvent: CCO
Product: O=C(CCN1CCCC1)Nc1ccc(Br)cc1

Procedure:
N-(4-Bromo-phenyl)-acrylamide (0.3 g, 1.33 mmol) was dissolved in ethanol. Pyrrolidine (0.12 ml, 1.46 mmol) was added and the mixture was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. Aqueous ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the desired product. Yield 0.24 g, 60%. LCMS method: 2, RT: 2.67 min; MI: 297-299 [M+1].
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[O-:23][CH2:24][CH3:25].[Na+]>CO>[CH2:24]([O:23][CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH3:25]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc(C)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (5 mL) and the solution was cooled to 0° C. (ice bath). Sodium ethoxide (0.10 g, 1.41 mmole) was added dropwise to the above solution, which was stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.16 g, 98%). No further purification was performed: GCMS m/z 344.00 (M+).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]2[O:14][CH2:13]2)[N:7]([CH2:15][CH:16]2[O:18][CH2:17]2)[C:6]1=[O:19])[CH:2]1[O:4][CH2:3]1.[OH2:20]>>[OH:20][CH:17]([OH:18])[CH2:16][CH2:15][N:7]1[C:6](=[O:19])[N:5]([CH2:1][CH:2]2[O:4][CH2:3]2)[C:9](=[O:10])[N:8]1[CH2:11][CH:12]1[O:14][CH2:13]1
Reactant: O
Reactant: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CC1CO1
Product: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CCC(O)O

Procedure:
5 g of triglycidyl urazole (0.019 mole) are stirred for 3 hours at 70° C. in 50 ml of water. The solution is concentrated in a rotary evaporator and dried in a high vacuum. The colourless, oily crude product (5.8 g) is purified by column chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1.[C:49]([CH2:51][CH2:52][O:53][C:54](ON1C(=O)CCC1=O)=[O:55])#[N:50]>CC#N.CCOC(C)=O>[C:49]([CH2:51][CH2:52][O:53][C:54]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1)=[O:55])#[N:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCN)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOC(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.3 %

Procedure:
To a solution of 2′-O-(5-aminopentyl)-5′-O-(4,4′-dimethoxytrityl)-adenosine (1.0 g, 1.52 mmol) in anhydrous CH3CN (8.0 mL) was added with stirring, under argon, N-(2-Cyanoethoxycarbonyl)oxy succinimide (0.43 g, 2.02 mmol) After stirring for 5 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with aq saturated bicarbonate (3×20 mL) and water (20 mL), dried (Na2SO4) and evaporated to give 53 as a light yellow foam (1.1 g, 98% yield). This compound was used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]=1[O:14][CH3:15].[B-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COC(=O)COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CO)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (4-Formyl-2-methoxy-phenoxy)acetic acid methyl ester 71 (50 grams, 223 mmol) in methanol (500 mL) at 0° C. was added Sodium boro hydrate (4 grams, 106 mmol) in small portions, further stirred at 0° C. for 30 minutes and poured on to ice water (200 mL). The pH of mixture was adjusted to 2 with concentrated hydrochloric acid. Crude 72 was extracted into chloroform, dried over Na2SO4 and distilled to give 72 (40 grams, 62%) as a light yellow syrup.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].[CH3:10][CH:11]([CH2:13][C:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]>>[CH3:10][CH:11]([CH2:13][C:14](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: NNc1cc(O)ncn1
Reactant: CC(C)CC(=O)CC(C)C
Product: CC(C)CC(CC(C)C)=NNc1cc(O)ncn1

Procedure:
10.00 g (79.3 mmol) 6-hydrazinopyrimidin-4-ol (CAS-No: 29939-37-5) were transformed in analogy to intermediate example 1c using 2,6-dimethylheptan-4-one to give after working up and purification 8.77 g (44%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[H][H]>[Ni].C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3ccc([N+](=O)[O-])cc3c2C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1

Procedure:
3-(Dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole is prepared by dissolving 0.1mole of 3-(dimethylamino)-6-nitro-1,2,3,4-tetrahydrocarbazole (Example 10) in 400 ml. absolute ethyl alcohol and hydrogenating over Raney nickel at about 350 psig and at room temperature until the required amount of hydrogen has reacted. The resulting 3-(dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole can be isolated and purified using conventional procedures.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][N:15]=[N+]=[N-])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][NH2:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN=[N+]=[N-])o1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(CN)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.9 %

Procedure:
To a solution of 88.6 mg of (5-azidomethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester in 3 mL of ethanol was added 30 mg of Lindlar catalyst, stirred at room temperature under hydrogen atmosphere for 15 hours, the catalyst filtered off, and the solvent was evaporated, to afford 81 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:41][C:42]4[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=4)[C:24]4[N:29]=[CH:28][C:27]([C:30]5[CH:31]=[N:32][N:33](C6CCCCO6)[CH:34]=5)=[CH:26][N:25]=4)[CH2:20][C@H:19]3[CH2:56][CH3:57])[C:15]([Cl:58])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.CO.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:41][C:42]4[CH:47]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:45]=[C:44]([C:52]([F:54])([F:55])[F:53])[CH:43]=4)[C:24]4[N:25]=[CH:26][C:27]([C:30]5[CH:34]=[N:33][NH:32][CH:31]=5)=[CH:28][N:29]=4)[CH2:20][C@H:19]3[CH2:56][CH3:57])[C:15]([Cl:58])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cnn(C6CCCCO6)c5)cn4)C[C@H]3CC)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cn[nH]c5)cn4)C[C@H]3CC)n2)CC1
Temperature: 25 °C

Procedure:
A 25 ml round-bottom flask was charged with 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester (70 mg, 0.084 mmol), 1N HCl (0.8 ml, 0.8 mmol) and MeOH (2 ml). The mixture is then heated to 60 degree for 30 minutes. After cooling down to rt, Saturated NaHCO3 and dichloromethane are added, then organic layer is collected. Removal of solvent give 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester and it is used for the next step without further purification.