Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[CH2:13]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][C:3]1[CH:4]=[C:5]([O:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC[C@@H](C)Oc1ccc(F)c(CO)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](C)Oc1ccc(F)c(CCl)c1
Temperature: 78 °C

Procedure:
To a solution of (2-fluoro-5-{[(1R)-1-methylpropyl]oxy}phenyl)methanol (0.091 g, 0.459 mmol) in carbon tetrachloride (4.59 ml) was added triphenylphosphine resin (0.241 g, 0.918 mmol). The reaction was heated to 78° C. overnight in a pressure tube with minimal stirring. The reaction mixture was filtered through a fritted funnel and washed with carbon tetrachloride. The filtrate was concentrated to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH3:21])=[N:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH3:21])=[N:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1ccc2c(c1)N=C(C)c1ccc(OC)cc1O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)Oc1ccc(C(=O)O)cc1N=C2C
Yield: 92.3 %

Procedure:
One gram of ethyl 3-methoxy-11-methyldibenzo[b,f][1,4]oxazepin-8-carboxylate was dissolved in 10 ml of methanol. To the solution, 10 ml of 1N sodium hydroxide was added and the mixture was refluxed for 1 hour. After cooling, the mixture was neutralized with dilute hydrochloric acid and the precipitating crystal was recovered by filtration. Recrystallization from methanol produced 0.84 g of 3-methoxy-11-methyldibenzo[b,f][1,4]oxazepin-8-carboxylic acid (Compound No. 1). Yield, 92%; melting point, 247° C. (with decomposition).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:20]([O:19][P:17]([CH2:16][P:11]([O:13][CH2:14][CH3:15])([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:25])=[O:3])=[CH:10][CH:9]=1)=[O:12])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[(Diethoxyphosphorylmethyl)-ethoxyphosphinoyl]-benzoic acid ethyl ester (3c) (1 g, 2.55 mmol) in methanol (25 mL) was slowly added lithium hydroxide (monohydrate, 0.11 g, 2.55 mmol) in water (25 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (3d) was purified by silica gel flash chromatography as a pale yellow oil (0.91 g). 1H NMR (300 MHz, DMSO-d6) δ (ppm)): 1.13 (m, 9H), 2.94 (t, J=18.2 Hz, 2H), 3.85 (m, 6H), 7.88 (m, 2H), 8.02 (m, 2H), 12.60 (bs, 1H), 31P NMR (121 MHz, DMSO-d6) δ, 37.59 and 24.59
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([O-:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.OS(O)(=O)=O>CC(O)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)[O-])cn2CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a suspension of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (458 mg, 1.21 mmol) in a mixture of AcOH (1.8 mL) and water (1.5 mL), was added H2SO4 (0.3 mL), the whole mixture was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were suspended in water, filtered, and dried in vacuo to give 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylic acid (401 mg, 95%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.FC(F)(F)C(O)=O.[Br:26]N1C(=O)CCC1=O>C(#N)C>[Br:26][C:3]1[C:2]([Cl:1])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(Br)cc21
Temperature: 80 °C
Yield: 45.4 %

Procedure:
To a solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.2 g, 0.773 mmol) in acetonitrile (4 mL) at −30° C. was added trifluoroacetic acid (0.089 mL, 1.160 mmol) and 1-bromopyrrolidine-2,5-dione (0.151 g, 0.850 mmol). The mixture was heated to 80° C. overnight. The reaction mixture was concentrated, diluted with ethyl acetate and excess aqueous 10% NaHCO3. The ethyl acetate layer was concentrated. The residue was purified by prep. HPLC to afforded 9-bromo-8-chloro-4,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (120 mg, 0.351 mmol, 45% yield) as white solid. LC/MS (ESI) m/e 337.0 [(M+H)+, calcd for C14H11BrClN2O, 337.0]; LC/MS retention time (Method C): tR=2.55 min; 1H NMR (400 MHz, METHANOL-d4) ppm 3.11 (s, 3H), 3.75 (s, 3H), 7.81 (s, 1H), 8.20-8.26 (m, 1H), 8.68 (d, J=5.6 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])(=[O:21])[NH2:2]
Reactant: CC(=O)O
Reactant: N#Cc1cc2n(c1)CCc1ccccc1C2=O
Agent: Cl
Product: NC(=O)c1cc2n(c1)CCc1ccccc1C2=O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-Cyano-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid was refluxed for 2 hours. It was then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution, from which crystals deposited during the extraction, was left to cool to room temperature and filtered to afford 2-carbamoyl-6,11-dihydro-11-oxo-5H-pyrrolo[2,1-b]-[3]benzazepine (27 g. 83%), m.p. 228° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:30])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[CH3:32][N:33]1[C:37]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:41]=[CH:42][C:43]=2[OH:44])=[CH:36][CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[C:3]([O:44][C:43]2[CH:42]=[CH:41][C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:39][C:38]=2[C:37]2[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:4][C:5]([F:30])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccc(F)cn2)cc1Cl
Reaction time: 2 h
Yield: 63.3 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 105, 23 mg, 0.04 mmol), 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 107, 9 mg, 0.04 mmol) and potassium carbonate (15 mg, 0.11 mmol) in dimethyl sulfoxide (1 mL) were stirred at room temperature for 2 hours. The mixture was treated with aqueous 2M HCl (3 mL). The resulting mixture was extracted with dichloromethane (3 mL). The dichloromethane layer was dried through a phase separating cartridge followed by treatment with trifluoroacetic acid (500 μL). The mixture was stirred for 2 hours and allowed to stand at room temperature for 18 hours. The mixture was then treated with a saturated solution of ammonium chloride (5 mL). The dichloromethane layer was separated, dried through a phase separating cartridge and evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound (14 mg, 45%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.[IH:32]>C(OCC)C>[IH:32].[CH3:24][N:20]([N:19]1[C:18]2[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)N(C)n1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane (0.18 g, 0.48 mmol) and dichloromethane (10 mL). Add hydriodic acid (0.17 mL, 57%, 0.95 mmol) and warm to 40° C. After 3 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Combine the residue and diethyl ether with stirring to give a solid. Collect the solid by filtration to give, after drying, the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]([CH2:40][C:41](=O)[CH3:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:41](/[CH3:42])=[CH:40]\[C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[N:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 32 mg (0.194 mmol) of benzoylacetone to yield 55 mg of Example 44: TLC (DCM/MeOH (4:1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.5 (d, 1H, J=9.0), 7.85 (m, 4H), 7.45 (m, 3H), 7.18 (d, 2H, J=8.4); 7.06 (d, 2H, J=8.8), 6.87 (d, 2H, J=8.5), 5.82 (s, 1H), 4.74 (m, 1H), 4.19 (t, 2H, J=6.6), 4.1 (m, 1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.81 (dd, 1H, J=13.9. 9.1), 2.36 (s, 3H), 1.74 (s, 3H), 1.34 (d, 6H, J=6.0); low resolution MS (ES−)m/e 567.2 (M-)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15]Br)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:11]1[N:10]=[CH:9][C:8]2[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1CCc2cc(NC(=O)C(C)(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl{4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate (6.5 g, 16.3 mmol) in tetrahydrofuran (50 mL) cooled in a dry ice-acetone bath was treated with a solution of lithium diisopropylamide in tetrahydrofuran (50 mL) (prepared from diisopropylamine (3.79 g, 34.7 mmol) and n-butyllithium (2.5 M, 13.7 mL) dropwise via addition funnel over 1 h. After complete addition, the reaction stirred an additional 1 h, then was quenched with saturated sodium bicarbonate solution and allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate and water and transferred to a reparatory funnel. The layers were separated and the aqueous extracted with ethyl acetate (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the resulting residue (2−>25% EtOAc/hexanes eluent) provided tert-butyl 3-[(2,2-dimethylpropanoyl)amino]-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate. 1H NMR (500 MHz, CDCl3), δ 8.27 (s, 1H), 8.16 (s, 1H), 8.06 (br s, 1H), 3.96 (dd, J=5.0, 5.5 Hz, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.45 (m, 1H), 2.32 (m, 1H)-1), 1.47 (s, 9H), 1.32 (s, 9H); LC/MS (M+1)+=319.0;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 53.3 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), [4-(trifluoromethyl)phenyl]acetic acid (120 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (82 mg, 53%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[F:10].[F:11][CH:12]([F:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(#N)C.Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH:12]([F:15])[F:11])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CCl)cnc1Cl
Reactant: NCC(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cc(CNCC(F)F)cnc1Cl
Yield: 57 %

Procedure:
At 45° C., 520 mg (2.89 mmol) of 6-chloro-3-chloromethyl-5-fluoropyridine (VII-3), 1.05 ml (14.44 mmol) of 2,2-difluoroethylamine and 400 μL (2.89 mmol) of triethylamine are stirred in 50 ml of acetonitrile for about 48 hours. After about 16 and 32 hours, in each case another 0.42 ml (5.78 mmol) of 2,2-difluoroethylamine are added. After concentration of the reaction mixture under reduced pressure, the residue is taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. The combined organic phase is dried over sodium sulphate and concentrated under reduced pressure, giving 370 mg (57% of theory) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:18][CH3:24])=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
A mixture containing 12.46 g of 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid and a catalytic amount of p-toluenesulfonic acid in 70 ml of methanol is boiled under reflux for 4 hours. After evaporating the solution to dryness, the residue is dissolved in ether and washed with sodium hydrogen carbonate solution. The ethereal layer is separated, dried over anhydrous magnesium sulfate and evaporated to dryness to give 11.5 g of product.
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:7]=3[N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:7]=3[N:8]=[C:9]([CH2:11][O:12][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: CN(c1nc(CO)nc2sc3c(c12)CCCC3)C1CC1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1nc(COc2cccnc2)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.1 %

Procedure:
To a mixture of [4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-methanol (0.25 g, 0.00086 mol), 3-hydroxypyridine (0.090 g, 0.00095 mol) & triphenylphosphine (0.24 g, 0.00095 mol) in THF (20 ml) was added DIAD (0.19 g, 0.00095 mol) in THF (5 ml), and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the resulting crude material was purified by preparative HPLC to give cyclopropyl-methyl-[2-(pyridine-3-yloxymethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine (35 mg, 11%) as a brown residue. 1H NMR (400 MHz, CDCl3): δ 0.35-0.42 (m, 2H), 0.62-0.68 (m, 2H), 1.72-1.78 (m, 2H), 1.88-1.97 (m, 2H), 2.80-2.90 (m, 5H), 3.00 (s, 3H), 5.24 (s, 2H), 7.16 (dd, 1H), 7.30 (dd, 1H), 8.17 (dd, 1H), 8.42 (d, 1H); LC-MS: [M+H]=367.3 m/z.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=O)=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:22][CH:21]1[CH2:23][CH2:24][CH2:18][CH:19]=[CH:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCO
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOCCOCC1C=CCCC1
Reaction time: 8 h

Procedure:
A 500 niL round bottom flask equipped with a mechanical stirrer was charged with 16.7g (0.15 mol) 2-butoxyethanol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, 39.9 g (0.15 mol) of 3-cyclohexene-1-methanol tosylate was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 mL), washed with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(N)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-(4-bromophenyl)propan-2-amine, hydrochloric acid (1.0 g, 4.0 mmol, AKOS) in DCM (30 mL) at about 0° C. was added TEA (1.11 mL, 7.98 mmol). A solution of BOC2O (1.623 ml, 7.01 mmol) in DCM (10 mL) was added dropwise over about 10 min. After about 30 min, the ice bath was removed and the mixture was stirred overnight at rt. The mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatograph (40 g silica gel column, 0-40% EtOAc/Heptane) to give tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate the title compound (1.13 g, 90%): LC/MS (Table 2, Method b) Rt=2.66 min.; MS m/z: 315 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CC(N(C)C)=O>[Br:8][C:9]1[C:17]2[C:16]([N:40]3[CH2:41][CH2:42][C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:39]3)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Triethylamine (3.55 mL, 25.45 mmol) was added to 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 61) (3.28 g, 8.48 mmol) and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (WO2008075109) (3.07 g, 11.88 mmol) in DMA (50 mL) at 20° C. The resulting suspension was stirred at 70° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with water (75 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (3.60 g, 69.7%) as a white solid.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N12CCN(CC1)CC2>C1C=CC=CC=1>[CH:17]1([NH:23][C:24]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: O=C=NC1CCCCC1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)N1C(=O)C2(CCCCC2)NC12CCCCC2

Procedure:
11.1 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 6.88 parts of cyclohexyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 150 parts of dry benzene were heated at reflux for 30 hours, cooled and filtered to remove N,N'-dicyclohexyl urea. The benzene filtrate was evaporated to dryness and the residue crystallised from petroleum ether of boiling range 80°-100°C to give 2.60 parts of 14-cyclohexylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one having a melting point of 106° to 109°C and the following analysis by weight: