Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(C)C=CC=CC=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(N)[C@H](N)C(C)C)=CC=1>CC(O)(C)C.CC(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([OH:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(N)(c2ccc(OC)cc2)[C@H](N)C(C)C)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanone (Example 9B, Step A; 85.0 g, 406 mmol) and 1.0 M KOtBu (8.11 mL, 8.11 mmol) in t-BuOH in IPA (200 mL) and toluene (50 mL) in a autoclave was added dichloro{(R)-(+)-2,2′-bis[di(3,5-xylyl)-phosphino-1,1′-binaphthyl}[(2R)-(−)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine (0.991 g, 0.81 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 520 psi with hydrogen. The reaction mixture was vigorously stirred at ambient temperature for 2 days (pressure was recharged to 520 psi when the internal pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (83.5 g, 97.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 77.2% e.e. (R)-enantiomer). (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoro ethanol (171 g, 808 mmol, 77.2% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (3410 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight. The resulting solid was collected by filtration, washed with hexane and dried to give (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (97.1 g, 56.8%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.9% e.e. (R)-enantiomer).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@@H:13]1Br)(=[O:10])[CH3:9]>[O-2].[Zn+2]>[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@H:13]1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Sc1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2)SC[C@H]1OC(C)=O
Yield: 32.2 %

Procedure:
If the procedure described in Preparation IV is followed starting from 4 g (36.3.10-3 mol) of benzenethiol, 15 g (42.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3 g (36.8.10-3 mol) of zinc oxide (ZnO), 4.5 g (yield: 32.29%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Li+].[Cl-].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1>C1COCC1.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]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:5]2[S:1][C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]=2[CH:6]=[O:7])=[CH:17][CH:16]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=Cc1csc2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(Cl)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Benzo[b]thiophene-3-carbaldehyde (27) (162 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. Pd(dba)2 (17 mg, 3 mol %) and P(o-furyl)3 (14 mg, 6 mol %) dissolved in THF (2 mL), and mixed with 1-chloro-4-iodobenzene (310 mg, 1.3 mmol, 1.3 equiv) were then transferred via cannula to the reaction mixture. The resulting mixture was stirred for 2 h at 25° C. The reaction mixture was then quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 29b (236 mg, 87%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15].[OH-].[Na+]>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)(=[O:16])=[O:15])[O:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Cc1noc(N)c1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide was prepared as described in Example 34B from 3,4-dimethyl-5-amino isoxazole (0.122 g, 1.0 mmol), furan-2-sulfonyl chloride (0.50 g, 3.0 mmol) and NaOH (64 mg). Flash chromatography (50% ethyl acetate/hexanes) yielded 70 mg of a yellow solid. Recrystallization from CHCl3 /hexanes produced an off-white solid (46 mg, 29% yield), m.p 107°-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][S:6](=[O:42])(=[O:41])[N:7]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([C:19]#[N:20])=[CH:14][CH:15]=2)[CH:10]=1)[CH3:2].CI.[C:46](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([N:7]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]#[N:20])=[CH:14][CH:15]=4)[CH:10]=3)[S:6]([CH:5]([CH3:46])[C:4]([O:3][CH2:1][CH3:2])=[O:43])(=[O:41])=[O:42])=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)=[O:35])([CH3:39])([CH3:38])[CH3:40]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C(C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 81.1 %

Procedure:
Ethyl[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]acetate (500 mg) was dissolved in 10 ml of acetonitrile, 0.52 ml of methyl iodide and 136 mg of potassium carbonate were added to the solution, and the mixture was stirred under reflux for 5 hours and 30 minutes. After cooling the reaction solution, the precipitate was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The resulting residue was applied to silica gel column chromatography, which was eluted with hexane:ethyl acetate (3:1) to give 415 mg of ethyl 2-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]propionate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[C:3]1([CH2:2][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc2c(CN3CCNCC3)cccc2c1

Procedure:
Synthesized according to General Procedure A: 1-(chloromethyl)naphthalene (4{24}, 5 mL, 33.4 mmol, 1 equiv.), piperazine (17.3 g, 200.6 mmol, 6 equiv.), THF (73.0 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{24} (6.58 g, 87%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.32 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.78 (d, 1H, J=8.0 Hz), 7.54-7.47 (m, 2H), 7.44-7.39 (m, 2H), 3.89 (s, 2H), 2.87 (t, 4H, J=5.0 Hz), 2.48 (br s, 4H), 1.68 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 134.3, 134.1, 132.8, 128.6, 128.1, 127.6, 125.9, 125.8, 125.3, 125.0, 62.0, 55.0, 46.4.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>>[C:4]1([CH:1]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
In some embodiments Scheme A can include reaction sequences as follows: Initially, 2,4,6-trihydroxyacetophenone is transformed into 2,4-dihydroxy-6-methoxyacetophenone using dimethyl sulphate as methylating agent. Then, the methyl group on the para-methoxy position of the acetophenone is cleaved using AlCl3, to obtain 2,4-dihydroxy-6-methoxyacetophenone, which is protected using allyl bromide to give 2,4-allyloxy-6-methoxylacetophenone. Claisen-Schmidt aldol condensation of acetophenone with the corresponding aromatic aldehyde in the presence of aqueous KOH, gives a chalcone product. After a mild deprotection procedure to remove the allyl-protecting groups, using Pd(PPh3)4 and K2CO3, the resulting 2′4′-dihydroxy-6-methoxy chalcones were finally reduced to produce the corresponding dihydrochalcones.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[F:17])[C:13](=[O:18])[CH:12]([CH2:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:21](OC)=[O:22])[CH2:11]2.Cl>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[F:17])[CH:13]([OH:18])[CH:12]([CH2:19][CH:20]([CH2:21][OH:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11]2
Reactant: CCCCCC(CC1Cc2cc(F)c(F)cc2C1=O)C(=O)OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCC(CO)CC1Cc2cc(F)c(F)cc2C1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
877 mg (23.1 mmol) of lithium aluminium hydride are initially introduced in 10 ml of THF, and a solution of 5.0 g (15.4 mmol) of methyl 2-(5,6-difluoro-1-oxoindan-2-ylmethyl)heptanoate in 20 ml of THF is added dropwise with ice-cooling. The cooling is removed, and the batch is left to stir at room temp. for 2 h and subsequently refluxed for 30 min. After hydrolysis using ice-water, the solution is acidified using conc. hydrochloric acid, and the aqueous phase is separated off and extracted three times with MTB ether. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, giving 5,6-difluoro-2-(2-hydroxymethylheptyl)indan-1-ol as a colourless oil, which is sufficiently pure for further reaction.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)=O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][C@H:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OC(C)C)CC1
Agent: O=C=O
Solvent: CO
Product: CC[C@H](Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OC(C)C)CC1

Procedure:
The racemic 1-methylethyl 4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy) propyl]-1-piperidinecarboxylate (prepared as in Example 142) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 80% CO2: 20% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as a white foam with Tr of 14.60 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:17]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]>CCOC(C)=O>[CH:17]([O:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Oc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3-Isopropoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-Isopropoxybenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-70% EtOAc in hexanes as eluant provided 140 mg (82%) of a yellow solid. MP 149-150° C., M+H=338
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][S:9][CH3:10]>CO>[CH3:1][O:12][C:11](=[O:13])[C@@H:6]([NH2:5])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: CC(=O)Cl
Reactant: CSCC[C@H](N)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)CCSC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At about 0° C., acetyl chloride (15 mL) was added dropwise to methanol (100 mL). After stirring for about 10 minutes at about 0° C., L-methionine (8.5 g, 57 mmol) was added and the resulting solution was stirred for about 10 minutes. The solution was then heated at reflux for about 4 hours, and then maintained at ambient temperature for about 16 hours. The solvent was removed in vacuo, the resulting residue was dissolved in chloroform (100 mL), and the solution was neutralized to pH 7-8 by the careful addition of a saturated aqueous sodium bicarbonate solution. Following standard extractive workup with chloroform, the resulting residue was kept under high vacuum for about two hours to afford the title product as a colourless oily liquid, which was used directly in the next step without any further purification (crude yield 6 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]2[OH:12]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(F)cc(C)cc2c1O
Temperature: 75 °C
Yield: 55.9 %

Procedure:
A mixture of 2-fluoro-4-methylaniline (5.0 g) and diethyl ethoxymethylene-malonate (8.64 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 75° C. and diphenyl ether (50 mL) is added. The solution is heated to 250° C. for 2 h with removal of ethanol by a Dean-Stark trap, then cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 5.564 g of ethyl 8-fluoro-4-hydroxy-6-methylquinoline-3-carboxylate. A mixture of this ester (0.50 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled and poured into 50 mL of diethyl ether. The resulting solid is filtered, dried, and purified by trituration in acetone to give the desired product (0.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.41 g, colorless oil) from 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanone (1.20 g, 5.03 mmol) and (R)-2-methylpropane-2-sulfinamide (914 mg, 7.54 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Br)c4)ncnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 42 h
Yield: 99.8 %

Procedure:
To a stirred heterogeneous mixture of compound 214 (2.92 g, 6.20 mmol) and DCM (60 mL) was added trifluoroacetic acid (4.75 mL, 62.0 mmol), followed by anisole (1.36 mL, 12.4 mmol), and the mixture was stirred further at room temperature for 42 h. It was poured into petroleum ether (600 mL) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). To the solid left behind was added 5M NH3 (80 mL) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 mL), petroleum ether-ethyl acetate=3:1 (3×20 mL), and dried to give N4-(3-bromo-4-chlorophenyl)pyrido[3,4-d]-pyrimidine-4,6-diamine (223) (2.17 g, 100%), mp 271-274° C.; 1H NMR δ [(CD3)2SO] 9.82 (s, 1H), 8.72 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.42 (s, 1H), 7.97 (dd, J=8.8, 2.3 Hz, 1H, 7.62 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C13H9BrClN5.0.6H2O: C, 43.20; H, 2.85; N, 19.38. Found C, 43.00; H, 2.95; N, 19.12.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C@@H:25]1([NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH2:31].[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[N:40]([CH3:44])[N:39]=[C:38]2[C:45]1[N:46]=[C:47]2[C:53]([C:54](O)=[O:55])=[CH:52][N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:48]2=[N:49][CH:50]=1>CN(C=O)C>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:32][C:54]([C:53]1[C:47]2[C:48](=[N:49][CH:50]=[C:45]([C:38]3[C:37]4[C:41](=[CH:42][CH:43]=[C:35]([O:34][CH3:33])[CH:36]=4)[N:40]([CH3:44])[N:39]=3)[N:46]=2)[N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:62])([CH3:64])[CH3:63])[CH:52]=1)=[O:55]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCCC[C@@H]1N)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and (1R,2S)-cyclohexane-1,2-diamine (20.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give the desired N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 38.2 μmol, 21.7%). MS (M+H)+=550 (>90% purity); 1H NMR (CDCl3) δ: 9.02 (s, 1H), 8.51 (s, 1H), 7.51 (s, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.22 (dd, J=9.3, 2.1 Hz, 1H), 5.61-5.84 (m, 2H), 4.78 (br. s., 1H), 4.18 (s, 3H), 4.02 (t, J=3.2 Hz, 1H), 3.91 (s, 3H), 3.76 (br. s., 1H), 3.62-3.71 (m, 2H), 2.09 (br. s., 2H), 2.03 (s, 2H), 1.80-1.98 (m, 4H), 1.52-1.78 (m, 4H), 0.98 (dd, J=9.3, 7.4 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([NH:17][C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14][N:13]([CH3:29])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C@H:11]3[C@H:16]([CH2:15][CH2:14][N:13]([CH3:29])[CH2:12]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc([C@@H]2CN(C)CC[C@@H]2NC(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc([N+](=O)[O-])cc1

Procedure:
cis-3-(3,4-Dimethoxypheny)-1-methyl-4-(4-nitrobenzoylamino)-piperidine [M.P. 167°, see Example 4 a)] is cyclized in analogy to the process described in Example 8. The dihydrochloride of the title compound has a M.P. of 225°-230° (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[B-](F)(F)(F)[O+](C)C.[O:17]=[C:18]1[CH:23]=[CH:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.[NH4+].[Cl-].[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:22]2[CH2:23][C:18](=[O:17])[CH2:19][CH2:20][N:21]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)CC1
Agent: C[O+](C)[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
CuBr.SMe2 complex (1.49 g, 7.26 mmol) was added to 25 mL of anhydrous THF and cooled to −78° C. 4-Chlorophenylmagnesium bromide (7.26 mL, 1.0 M in THF, 7.26 mmol) was added slowly via syringe. Stirring at −78° C. for 1 hour produced an orange then green-like suspension. Boron trifluoride dimethyl etherate (0.92 mL, 7.26 mmol) was added and stirred for 5 minutes. To the newly formed complex was then added over 1 hour a solution of the compound 66 (1.0 g, 4.32 mmol) in 15 mL of anhydrous THF. After stirring 2 hours at −78° C., 16 mL of aq. 20% NH4Cl/conc. NH4OH (1:1) was added, and the mixture was allowed to warm-up to room temperature. EtOAc was used to extract (3×100 mL) and the combined organic layers were washed with brine and dried (MgSO4). Solvent was removed by rotary evaporation and the residue was purified by flash chromatography to give the product 67 as a colorless oil.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][O:17]C(=O)C)[C:6]=2[N:7]=[CH:8][N:9]=1.CO.N>C(Cl)Cl>[Cl:3][C:4]1[C:5]2[C:12]([I:1])=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: ClI
Reactant: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Agent: N
Solvent: CO
Solvent: ClCCl
Product: OCCOCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Iodine monochloride (0.38 mL) was added dropwise with stirring under a nitrogen atmosphere to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3, 0.82 g) in dry CH2Cl2 (25 mL). The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated at 40 degrees C. under high pressure and the dark purple syrup was placed on the top of a silica gel column. Elution of the column (15×2 cm) with CHCl3 yielded a dark colored syrup, after evaporation of the appropriate UV absorbing fractions, which on trituration with dry ether gave a crystalline product. (0.3 g) as colorless needles. These needles were covered with methanol saturated with ammonia (30 mL) at 0 degrees C., and the reaction mixture stirred at room temperature in a pressure bottle for 20 hours. The solvent was evaporated under high vacuum and the resulting solid was recrystallized from methanol to furnish colorless needles of 9b, 0.21 g (80.75%), mp 154- 155 degrees C. 1H-NMR (DMSO-d6): 8.69 (s, 1, C2-H), 8.14 (s, 1, C6-H), 5.66 (s, 2, N7-CH2), 4.57 (t, 1, J=3.0 Hz, 3.3 Hz, exchangeable with D2O, OH), 3.46-3.33 (m, 4, CH2): UVλmax nm (ε×104); (pH 7) 225 (1.8), 296 (0.9); (pH 1) 233 (2.1), 280 (0.95); (pH 11) 228 (0.8), 280 (0.85).