Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:10][CH:11]1[CH2:23][C:22]2[C:14](=[CH:15][C:16]3[CH2:20][CH2:19][O:18][C:17]=3[CH:21]=2)[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)=O.[OH-].[Na+]>[CH2:3]([N:10]([CH:11]1[CH2:23][C:22]2[C:14](=[CH:15][C:16]3[CH2:20][CH2:19][O:18][C:17]=3[CH:21]=2)[CH2:13][CH2:12]1)[CH3:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: c1ccc(CNC2CCc3cc4c(cc3C2)OCC4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN(Cc1ccccc1)C1CCc2cc3c(cc2C1)OCC3
Temperature: 0 °C

Procedure:
44 ml of 37% strength formaldehyde solution in water are added to a solution of 21 g of the compound of Example 7 in 26 ml of concentrated formic acid maintained at 0° C. After 2 hours under reflux, the cooled reaction medium is diluted with 40% strength sodium hydroxide solution in water and extracted with methylene chloride. The organic phase is washed, dried and then evaporated under vacuum. The residue, purified by passage through a silica column, leads to the production of an oil. The elution solvent used is a mixture of methylene chloride and ethyl acetate (85:15 V/V)
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].[N-]=C=O>O>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([O:4][CH:1]([CH3:3])[CH3:2])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: CC(C)O
Agent: [H-]
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of isopropanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1isocyanatocyclohexane was added dropwise over 5 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was separated, washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 11.0 grams (81.5% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1725 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[C:16]([C:15]1[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=1[O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1C#N
Temperature: 90 °C

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (10.5 g), 2,6-difluorobenzonitrile (17.17 g) and Cs2CO3 (22.12 g) in dimethyl sulfoxide (150 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The solid was triturated with 7:3 hexanes/ethyl acetate (300 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel eluting from 15%-25% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:16])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([I:15])[CH:14]=1)[NH:11][CH:10]=[CH:9]2)#[N:2]>COCCOCCOC.CO>[I:15][C:13]1[C:12]2[NH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:6]([CH:14]=1)=[N:5][C:4]([NH2:16])=[N:3][C:1]=2[NH2:2]
Reactant: N#CN=C(N)Nc1cc(I)c2[nH]ccc2c1
Solvent: CO
Solvent: COCCOCCOC
Product: Nc1nc(N)c2c(cc(I)c3[nH]ccc32)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of N″-cyano-N-(7-iodo-1H-indol-5-yl)guanidine V (6.08 g, 18.7 mmol) in 2-methoxyethyl ether (50 mL) was heated to 175° C. for 32.5 h. The reaction mixture was cooled to 25° C., the resulting solids removed by filtration and washed with methanol. The filtrate was concentrated in vacuo to give a brown oil. The residue was dissolved in methanol and then absorbed onto Merck Silica gel 60, 230–400 mesh (25 g). Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10/1 methylene chloride/methanol/ammonium hydroxide) afforded 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine VI (3.61 g, 59%) as a brown solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.36 (broad s, 1H), 7.45 (broad s, 1H), 7.43 (t, J=2.93 Hz, 1H), 7.20 (s, 1H), 6.74 (broad s, 2H), 5.78 (broad s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:28])[O:9]2.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][C@@H:12]3[CH2:11][C@H:10]4[C@H:6]([CH2:7][C:8](=[O:28])[O:9]4)[C@H:5]3/[CH:4]=[CH:3]/[C@@H:2]([O:1][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1=COCCC1
Reactant: CCCCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)OC1CCCCO1

Procedure:
The 3S-hydroxy compound (4a) (4.58 g) was dissolved into methylene chloride (100 ml), and reacted with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid-1H2O. After a usual work-up, the reaction mixture was column-chormatographed to give the title compound (5). Yield: 5.03 g
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(O)(=O)C>CO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:28][CH2:29]2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
Sodium cyanoborohydride (440 mg; 7.0 mmol) was added to a solution of [(1-tert-butoxycarbonyl-4-piperidinyl)-methyl]amine (1.5 g; 7.0 mmol) in methanol (30 ml) under ice cooling, and the mixture was stirred for 15 minutes. A solution of 1-tert-butoxycarbonyl-4-piperidine-carbaldehyde (1.4 g; 9.1 mmol) in methanol (5 ml) and acetic acid (0.40 ml; 7.0 mmol) were added to the resultant solution, and the mixture was stirred for 4 hours. After the ice bath was removed, the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resultant concentrated residue was added to a saturated aqueous solution of sodium hydrogencarbonate to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 1.83 g (yield: 63%) of N,N-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]amine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH:16]([CH3:18])[CH3:17])[CH:12]([CH3:14])[CH3:13])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)NC(C)C
Product: CC(C)N(C(=O)c1ccc(Br)cc1F)C(C)C

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and diisopropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)c(Cl)nn2CCN1CCCC1
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-5-nitro-1H-indazole (1.5 g, 7.6 mmol) was treated with potassium carbonate (3.1 g, 23 mmol) in DMF (20 mL) for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine (1.9 g, 11 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.60 (m, 4H), 2.45 (m, 4H), 2.89 (t, J=6.44, 2H), 4.58 (t, J=6.44, 2H), 8.00 (m, 1H), 8.30 (m, 1H), 8.60 (m, 1H); MS (DCI/NH3) m/z 295 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:25]\[CH:26]([CH3:28])[CH3:27])/[C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Reaction time: 8 h
Yield: 188.2 %

Procedure:
(E)-Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (121 mg, 0.29 mmol) was dissolved in MeOH (10 mL) and DMSO (10 mL) and treated with 1 M NaOH (10 mL) at 100° C. After stirring overnight, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 200 mg (94% yield) of (E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoic acid. MS found: (M+H)+=367.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N:13]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:22](=[O:23])[C:21]3[CH:20]=[CH:19][C:18]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Reactant: Cc1ccc2ccc(N)cc2n1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-n4cccn4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(1-pyrazolyl)benzoic acid (47 mg, 0.25 mmol) as an off-white solid. MS (ES): MH+ 329, M-H+ 327.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:18]=1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(Br)cc1
Product: COc1ccc(Nc2ccc(C#N)cc2)c(C(F)(F)F)c1
Yield: 60.5 %

Procedure:
Analogously to Example 1a), 4-bromobenzonitrile was reacted with 2-trifluoromethyl-4-methoxy-aniline. After chromatographic purification through silica gel (petroleum ether with 10 to 30% ethyl acetate) the 4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile was obtained in a yield of 60.5% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:16])([CH2:9][CH2:10]C(OCC)=O)[CH:3]1[CH3:17].[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:16])([CH2:9][CH2:10][NH2:18])[CH:3]1[CH3:17]
Reactant: CCOC(=O)CCC1(C)C(C)CCN(C)C1C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CCN(C)C(C)C1(C)CCN
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Ethyl 1,2,3,4-tetramethyl-3-piperidinepropanoate (34.0 g, 141 mmol) was dissolved in concentrated sulfuric acid (300 mL) under a nitrogen atmosphere and the mixture was heated to 60° C. Sodium azide (18.35 g, 282 mmole) was then added in small portions (300-500 mg) over a three hour period at such a rate that a temperature range of 50°-70° C. was maintained. The mixture was then stirred at 60° C. for 2 hours, cooled to room temperature and poured onto ice-water (800 mL). The solution was basified with 35% NaOH and extracted with ether (3X). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo to afford 18.5 g (71%) of 1,2,3,4-tetramethyl-3-piperidineethanamine as a yellow oil. The product was treated with ethereal HCl to afford the product as a dihydrochloride salt. The salt was isolated as a white powder and had a melting point of 233°-235° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1.O>C[Si](C)(C)N[Si](C)(C)C.Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1)(=[O:7])[OH:6]
Reactant: O=C1CCC1
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: NCCCP(=O)(O)C1(O)CCC1

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to 15° and 2.0 ml of cyclobutanone are added. An exothermic reaction ensues. The reaction mixture is stirred until the temperature drops to room temperature (approximately 1 hour). Water is added and the volatile materials are removed in vacuo to yield a semi-solid. This is dissolved in 2.0M aqueous hydrochloride acid and washed with 2×100 ml of dichloromethane. The aqueous layer is evaporated in vacuo to afford a solid which is passed through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column to give 3-aminopropyl(1-hydroxycyclobutyl)phosphinic acid, m.p. 174°-175° (dec).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6](OC)=O)#[N:4].[Br:10][C:11]1[CH:18]=C[C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.Cl>CS(C)=O.O>[Br:10][C:11]1[CH:18]=[CH:6][C:5]([C:3]#[N:4])=[C:13]([CH2:14][C:15]#[N:16])[CH:12]=1
Reactant: COC(=O)CC#N
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0° C. in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4-Bromo-2-fluorobenzonitrile (118 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 90° C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104° C. over 3 hours. 2.3 L of water was added and the mixture was heated at reflux 16 hours. The mixture was cooled to 5° C. and 700 mL of 0.2N HCl was added. The mixture was allowed to stir at 5° C. for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78%). LCMS (API-ES) m/z: 223, 221 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](I)=[C:6]([CH3:8])[CH:7]=1.Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.[Cu]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1cc(Br)cc(C)c1I
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1c(C)cc(Br)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a degassed solution of 5-bromo-2-iodo-1,3-dimethylbenzene (3.9 g, 12.54 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.22 ml, 25.08 mmol) in DMSO (30 ml) was added copper (3.19 g, 50.2 mmol). The reaction mixture was stirred at 60° C. for 3 h, then cooled to r.t. and filtered. The filtrate was diluted with EtOAc and water, extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified by flash chromatography to give Intermediate 7A (3.4 g, 11.07 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.32 (t, J=7.03 Hz, 3H) 2.44 (t, J=4.17 Hz, 6H) 4.32 (q, J=7.18 Hz, 2H) 7.23 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.28 (br. s., 2F).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@:12]1([C:17]1[NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:24]=2[CH:25]=1)[CH3:16])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:16][C@:12]1([C:17]2[NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[C:24]=3[CH:25]=2)[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: [H][H]
Reactant: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3C(=O)OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3)cc12
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A stirred mixture of (R)-methyl 2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mol), methanol (10 mL), and 10% palladium on carbon (50 mg) was treated with a balloon-pressure of hydrogen at room temperature. After 2 hours, the mixture was filtered through Celite and the filtrate was concentrated to give (R)-methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg, 94%). 1H NMR (CDCl3-d1) δ 10.9 (s, 1H), 7.86 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.14 (s, 1H), 3.96 (s, 3H), 3.40-3.43 (m, 1H), 3.12-3.15 (m, 1H), 2.78-2.81 (m, 1H), 2.23-2.26 (m, 3H), and 1.94 (s, 3H). MS (ESI) m/e [M+1]+ 259.0.
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd]>[CH2:1]([OH:11])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Product: CCCCCCC/C=C\CO
Yield: 87 %

Procedure:
To a solution of 10.0 g of 2-decyn-1-ol in 150 ml petroleum ether was added 500 mg of Pd on CaCO3 poisoned with lead (Lindlar catalyst). Quinoline (2.0 ml) was then added to this mixture and the flask was evacuated (house vacuum, ca. 50 mm Hg) and flushed with H2 three times and left under a H2 atmosphere. The mixture was stirred vigorously until uptake of H2 was no longer evident and TLC (SiO2 /20% ether:pet. ether) showed no starting material. The catalyst was removed by filtration through a 4 cm pad of celite and the filtrate was washed two times with 100 ml of 1N HCl, once with 100 ml of saturated NaHCO3, once with 100 ml of brine, dried over MgSO4, filtered and the solvent evaporated to give a pale yellow oil. Kugelrohr distillation (100°-120° C. oven, 0.2 mm) affords 8.81 g of clear oil. 1H NMR δ 5.57 (m,2), 4.20 (t, 2, J=5 Hz), 2.07 (dd, 2, J=6, 12 Hz), 1.5-1.1 (m, 10), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:19])([CH:16]([F:18])[F:17])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][C:13]([F:19])([F:12])[CH:16]([F:18])[F:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCC(F)(F)C(F)F
Product: O=C(O)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (7.29 g, a pale brown solid) from 5,6-dichloronicotinic acid (5.00 g, 26.0 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (5.16 g, 39.1 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[N:16]1([C:14](=[O:15])[CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:22])[C:4]([OH:23])=[O:3])=[CH:11][CH:10]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
4-[2-(4-Morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.4 g) in methanol (70 mL) was treated with sodium carbonate (0.158 g) in water (2 mL), and the mixture was stirred at room temperature for 1.5 hours. After the solvents were removed in vacuo, dichloromethane (40 mL) and water (40 mL) were added and the mixture was acidified with 3N hydrochloric acid. Tetrahydrofuran was added to dissolve the solids, then the separated aqueous layer was extracted twice with dichloromethane-tetrahydrofuran (1:1). The combined organic layers were dried (MgSO4), evaporated, and the residual solid was crystallized from dichloromethane-tetrahydrofuran-hexane to yield 0.36 g of 4-[2-(4-morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 182°-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCNC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate (0.8 g, 1.7 mmol) in dichloromethane (25 ml) at 0° C. was added trifluoroacetic acid (5 ml). The reaction mixture was warmed to room temperature and stirred at room temperature for 20 hr. The solvent was evaporated and dilute NaOH added (5N, 10 ml). The resulting residue solution was extracted with EtOAc (3×50 ml) and the combined organics were washed with brine (1×75 ml). The organic solution was dried (sodium sulphate), filtered and evaporated in vacuo to leave 5-(4-phenoxyphenyl)-7-(3-pyrrolidinyl) -7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as a white solid (0.5 g, 79%) m.pt. 182-184° C. Rf in 1:1 EtOAc : MeOH=0.15. 1H NMR (d6 DMSO, 250 MHz): 8.14 (1H, s), 7.37-7.50 (5H, m), 7.05-7.18 (5H, m), 6.14 (2H, bs), 5.23 (1H, m), 3.09-3.27 (2H, m), 2.83-2.98 (2H, m), 2.19-2.33 (1H, m), 1.88-2.01 (1H, m). Mass spec. 371.1758 (C22H2 ON5). IR (KBr disc): 3106, 1585, 1489, 1232 cm−1.