Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1ccncc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccncc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 4-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 121°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]([Si:17]([CH3:30])([CH3:29])[O:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl>[CH3:16][C:14]([Si:17]([CH3:30])([CH3:29])[O:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[S:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])([CH3:13])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.7 %

Procedure:
The following process was carried out according to literature precedent (JOC, 1988, 53 (7), 1372). 2,4-Difluorobenzenesulphonyl chloride (436 mg, 2.05 mmol) was added slowly to a stirred solution of 2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N-(phenylmethyl)ethanamine (600 mg, 2.26 mmol) in a 1:1 mixture of 10% sodium hydroxide solution and DCM (80 mL) at 0° C. The reaction mixture was allowed to warm up to RT and left to stir for 5 hours. The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title compound as a colourless oil (939 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(N(CC)CC)C>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCc1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The 2-[2-(2,4-difluorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was dissolved in 40 ml of dichloromethane containing 1.13 g of triethylamine and the solution was treated with 1.28 g of methanesulfonyl chloride. After stirring for 15 minutes, the solution was washed well with water, the organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 3.12 g (100%) of 2-[2-(2,4-difluorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:24])[O:13][CH2:12][C@H:11]([NH:25]C(OC(C)(C)C)=O)[C:10](=[O:33])[O:9][C@H:8]1[CH3:34])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[OH:36][C:37]1[C:38]([C:45]([OH:47])=O)=[N:39][CH:40]=[CH:41][C:42]=1[O:43][CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CCOC(C)=O>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:14](=[O:24])[O:13][CH2:12][C@H:11]([NH:25][C:45](=[O:47])[C:38]2[C:37]([OH:36])=[C:42]([O:43][CH3:44])[CH:41]=[CH:40][N:39]=2)[C:10](=[O:33])[O:9][C@H:8]1[CH3:34])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)OC(C)(C)C
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC(=O)OC(C)(C)C)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Temperature: 22 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
To a solution of (3S,6S,7R,8R)-8-(2-tert-butoxy-2-oxoethyl)-3-(tert-butoxycarbonylamino)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (130 mg, 0.267 mmol) in EtOAc (3 mL) was added 1M HCl in EtOAc and the solution was stirred at room temperature (about 22° C.) for 6 h. The solvent was evaporated and the residue was dissolved in CH2Cl2 (1.5 mL). To this solution was added 3-hydroxy-4-methoxypicolinic acid (58 mg, 0.345 mmol), HATU (139 mg, 0.367 mmol) and N-methylmorpholine (120 mL, 1.09 mmol), sequentially. The reaction was allowed to stir at ambient temperature for 12 h and then loaded directly onto a SiO2 column and purified by flash chromatography (hexanes/EtOAc gradient) to give the title compound (62 mg, 43%) as a white solid: mp 192-194° C.; 1H NMR (400 MHz, CDCl3) δ 11.79 (d, J=0.5 Hz, 1H), 8.63 (d, J=8.3 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 6.89 (d, J=5.1 Hz, 1H), 5.45 (s, 1H), 5.21 (dd, J=15.5, 8.3 Hz, 1H), 5.12-5.01 (m, 1H), 5.01-4.87 (m, 1H), 3.95 (s, 3H), 3.80 (d, J=25.0 Hz, 1H), 2.98 (ddd, J=11.8, 9.9, 3.2 Hz, 1H), 2.86-2.74 (m, 1H), 2.62 (dt, J=14.0, 7.0 Hz, 1H), 2.35-2.23 (m, 1H), 1.41 (s, 9H), 1.30 (dd, J=6.2, 2.4 Hz, 3H), 1.22 (dd, J=7.0, 1.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.50, 172.00, 170.26, 169.90, 169.01, 155.45, 148.86, 140.73, 129.97, 109.74, 81.74, 74.79, 74.07, 65.03, 56.13, 49.80, 45.81, 34.93, 34.02, 27.97, 18.96, 18.84, 17.79; ESIMS m/z 539 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:21](OC)=[O:22])[C:17]([O:19][CH3:20])=[O:18]>CC(O)C>[OH:22][C:21]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Temperature: 90 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (3.0 g, 13 mmol) produced in Example 11-B (v) and dimethyl chloromalonate (6.6 g, 40 mmol) in 2-propanol (40 mL) was stirred at 90° C. for 7 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with ethyl acetate and diisopropyl ether and dried to give the title compound (3.1 g, 82%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][OH:26])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29].[CH3:30]I.O>CN(C)C=O>[Br:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N:22]([C:24](=[O:27])[CH2:25][O:26][CH3:30])[CH3:23])[C:16]=3[Cl:28])[C:7]2=[N:6][C:5]=1[CH3:29]
Reactant: CI
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 9 mg) in N,N-dimethylformamide (1 ml) was added 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg). After stirring for 10 minutes, methyl iodide (36 mg) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture were added methyl iodide (36 mg) and N,N-dimethylformamide (1 ml). The mixture was stirred at 60° C. for additional 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layers were washed with water 4 times and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane: methanol=20:1, V/V) followed by crystallization from ethanol-diethyl ether to give 3-bromo-8-[3-(N-methoxyacetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (20 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:17]([O:21]CC2C=CC=CC=2)=[CH:16][C:3]=1[O:4][C:5]1[C:13]2[CH2:12][C:11](C)(C)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:29]([OH:31])[CH3:30]>[Pd]>[CH3:9][C:13]1([CH3:5])[O:31][C:29]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:5][O:4][C:3]3[CH:16]=[C:17]([OH:21])[CH:18]=[C:19]([Cl:20])[C:2]=3[Cl:1])=[CH:8][CH:7]=[CH:6][C:30]=2[CH2:12]1
Reactant: CC1(C)Cc2c(Oc3cc(OCc4ccccc4)cc(Cl)c3Cl)cccc2O1
Reactant: CCO
Agent: [Pd]
Product: CC1(C)Cc2cccc(OCCCCOc3cc(O)cc(Cl)c3Cl)c2O1

Procedure:
A mixture of 0.5 gram (0.001 mole) of 7-{4-[2,3-dichloro-5-(phenylmethoxy)phenoxy}-2,2-dimethyl-2,3-dihydrobenzo[b]furan and 0.1 gram (catalyst) of 10% palladium on carbon in 75 mL of ethanol was placed in a Parr hydrogenation bottle and hydrogenated using a Parr hydrogenation apparatus. Upon the theoretical uptake of hydrogen gas, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 100% methylene chloride, then 5% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.17 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: BrC1OC(C2N=C3C=CC(C#N)=CN3C=2)=CC=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=O)[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1>CCO>[Br:37][C:34]1[CH:35]=[CH:36][C:31]2[N:32]([CH:25]=[C:24]([C:23]3[CH:28]=[CH:29][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:30]=2)[CH:33]=1
Reactant: Nc1ccc(Br)cn1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Solvent: CCO
Product: N#Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Yield: 62 %

Procedure:
The same procedure described for 3a was used employing 4-Cyanophenacyl bromide and 2-Amino-5-bromopyridine. Yield 62%, mp 218-219° C. (EtOH). 1H NMR (DMSO-d6); δ 7.41 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 8.15 (d, J=8.4 Hz, 2H), 8.53 (s, 1H), 8.92 (s, 1H). 13C NMR; δ 143.5, 143.0, 137.9, 132.7, 128.5, 127.1, 126.1, 118.8, 117.9, 111.3, 110.0, 106.4. MS (m/z, rel.int.); 298 (M+, 100). Anal. (C14H8BrN3) C, H.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(F)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)c(F)c1F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2F)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:37][CH3:38])[CH:12]=1.[CH3:39][N:40]1[CH2:44][C@@H:43]2[NH:45][CH2:46][CH2:47][C@@H:42]2[CH2:41]1>FC(F)(F)CO>[CH3:39][N:40]1[CH2:41][C@@H:42]2[C@@H:43]([N:45]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:29]([CH3:36])[CH:28]=5)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:37][CH3:38])[CH:12]=3)[CH2:46][CH2:47]2)[CH2:44]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 84.3 %

Procedure:
DIPEA (0.411 mL, 2.36 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 425 mg, 0.94 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 250 mg, 1.98 mmol) in 2,2,2-trifluoroethanol (4 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave impure title compound (396 mg, 84%) as an orange/red solid. This solid was dissolved in the minimum amount of CH2Cl2 and the resulting solution was triturated with methanol. The resulting solid was collected by filtration to give the title compound (272 mg, 58%) as a red solid which was used without further purification; 1H NMR: 1.86 (1H, dd), 1.94-2.06 (1H, m), 2.12 (3H, s), 2.23 (1H, dd), 2.36-2.45 (2H, m), 2.52-2.58 (1H, m) partially obscured by DMSO peak, 2.91-3.04 (1H, m), 3.18 (1H, t), 3.49 (1H, td), 3.87 (3H, s), 3.95 (3H, s), 4.40 (1H, t), 6.61 (1H, s), 7.11 (1H, t), 7.18 (1H, d), 7.24 (1H, t), 7.51 (1H, d), 8.02 (1H, s), 8.27-8.31 (2H, m), 8.34 (1H, d), 8.51 (1H, s); m/z: ES+ MH+ 500.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:38]1CCC[C@@H]1CNC1N=C2C(NC(=O)N2C2C=CC=CC=2OC)=C(C(OCC)=O)N=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)=[N:13][C:14]=2[C:19]([NH2:38])=[O:21]
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.381 g, 0.744 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred for two h and condensed under reduced pressure to afford the crude title compound (0.420 g, >100%). MS (ESI) m/z 413.1 [M+1]+.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>>[CH2:1]([O:16][C:13]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)ccc1O
Product: CCOC(=O)c1cc(OCC)ccc1O
Yield: 69.8 %

Procedure:
Using the general method of Example XXIII Part A, 31.2 g (0.20 mole) of ethyl iodide was reacted with 27.3 g (0.15 mole) of ethyl 2,5-dihydroxybenzoate to provide 22 g of white crystalline ethyl 5-ethoxy-2-hydroxybenzoate, m.p. 64°-66° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20](C)C)[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:26][C:27]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:35][N:33]([CH3:34])[C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[F:26]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(F)c(N(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-dimethyl-amine (stage 151.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.59 min (Method A); M+H=432 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.08 (m, 2H), 7.99-7.94 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.54 (m, 1H), 7.28-7.23 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 6H), 1.96 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=O)=[CH:9]2)=[CH:5][CH:4]=1.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](/[CH:17]=[CH:24]\[N+:21]([O-:23])=[O:22])=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(Cn2cc(/C=C\[N+](=O)[O-])c3ccccc32)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
1-(4-Methoxybenzyl)-1H-indole-3-carbaldehyde (I-61a: 22 g, 83.01 mmol) was refluxed overnight with nitromethane (146 g, 2407 mmol) and ammonium acetate (3.26 g, 42.33 mmol) to afford the crude product. The reaction mass was cooled to room temperature and filtered. The solid collected was washed with water and dried under reduced pressure to afford 20 g of the product (76% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:27][O:28][C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>ClCCl>[CH3:27][O:28][C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:33]=1
Reactant: COc1ccc(-c2oc3ncnc(Cl)c3c2-c2ccc(OC)cc2)cc1
Reactant: COC(=O)COc1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(OC)cc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 400 mg (1.091 mmol) of 4-chloro-5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidine (for preparation see WO 03/018589) and 237.1 mg (1.309 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, add dichloromethane to the residue and purify by means of silica gel (eluent: dichloromethane/ethyl acetate 10:1). 139.3 mg (25% of theory) of the target compound are obtained as a light yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(I)c(F)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(I)c(F)cc1F
Temperature: 60 °C

Procedure:
To a solution of 11 (74.0 g, 260 mmol) in toluene (370 mL) was added thionyl chloride (95 mL, 1300 mmol) in DMF (2.5 mL, 26 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to approximately 60° C. and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure and residual thionyl chloride was co-evaporated with toluene (2×120 mL) to give crude 12 which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCI
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E1 of 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (0.26 g, 1.3 mmol), acetonitrile (3 mL), potassium carbonate (0.269 g, 1.95 mmol) and iodopropane (0.22 g, 1.3 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 45:55 to 60:40). Yield: 0.156 g. [α]D=+19.0° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 127-129° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 9), 212, (bp), 182 (32), 141 (17), 84 (58).