Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[S:18]([C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:18]([C:21]([F:26])([F:25])[CH:22]([F:23])[F:24])(=[O:19])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)C(F)(F)C(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)C(F)(F)C(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 0 °C
Yield: 129.6 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)-4-[(1,1,2,2-tetrafluoroethyl)sulfonyl]pyrrole-2-carboxylate (0.54 g, 0.0012 mol) in ethanol is treated under nitrogen with a solution of sodium hydroxide (0.26 g, 0.0065 mol) in water. The reaction mixture is refluxed for three hours, poured into ice-water, treated with hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a gum (0.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](NC3C=NC4C(C=3)=CC=CC=4)[CH:9]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=1>CS(C)=O>[O:17]1[CH2:18][CH2:19][N:14]([C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)[CH:9]=[C:10]([O:43][C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[N:11]=2)[CH2:15][CH2:16]1
Reactant: Nc1ncc(-c2cc(Nc3cnc4ccccc4c3)nc(N3CCOCC3)n2)cn1
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(-c2cc(Oc3cccnc3)nc(N3CCOCC3)n2)cn1
Temperature: 110 °C
Yield: 42.7 %

Procedure:
5-(6-chloro-2-morpholinopyrimidin-4-yl)pyrimidin-2-amine (10 mg, 0.034 mmol, prepared as in example 1), potassium tert-butoxide (6 mg, 0.051 mmol), pyridin-3-ol (5 mg, 0.051 mmol) and DMSO (0.5 mL) were all combined together and heated at 110° C. for 2 days. The crude product was purified directly by preparative reverse phase HPLC to give 5-(2-morpholino-6-(pyridin-3-yloxy)pyrimidin-4-yl)pyrimidin-2-amine (5.1 mg, 32%). LC/MS (m/z): 352.1 (MH+), Rt 1.83 minutes.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH:27]4[CH2:29][CH:24]3[CH2:25][O:26]4)[N:18]2[CH3:21])=[C:14]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][O:26]3)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CC3CC2CO3)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC4CC3CO4)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-5-oxa-2-aza-bicyclo[2.2.1]heptane were reacted to give 384. LCMS m/z: 461.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[NH2:15])=[CH:7][CH:6]=1)=[O:4].C=O.[C:23]([BH3-])#N>CO.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[NH:15][CH3:23])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(COc2cc(C)ccc2N)cc1
Reactant: [BH3-]C#N
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CNc1ccc(C)cc1OCc1ccc(C(=O)OC)cc1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a mixture of 2-(4-methoxycarbonylphenyl)methoxy-4-methylaniline (420 mg) and 37% formaldeyde solution (69.7 mg) in a mixture of methanol (10 ml) and actic acid (0.1 ml) was added soduim cyanoborohydride (146 mg) and the mixture was stirred at amibient temperature for 3 hours. The solution was diluted with ethyl acetate (30 ml) and washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column (chloroform) to give 2-(4-methoxycarbonylphenyl)methoxy-4-methyl-N-methylaniline (356 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: Clc1ncccc1Br
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccnc1N1CCNCC1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-2-chloropyridine (0.96 g, 5 mmol, Aldrich), piperazine (0.86 g, 10 mmol, Aldrich) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) was heated in a microwave synthesizer for 40 min at 200° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 10% MeOH in dichloromethane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CO>[OH:1][CH:2]([CH2:18][NH:22][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: O=C1CCC(c2ccc(OCC3CO3)cc2)=NN1
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 99.9 %

Procedure:
A mixture of the 6-[4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (38.37 g, 0.156 mole), isopropylamine (80 ml, 0.94 mole), and methanol (380 ml) was stirred under reflux for one hour, and then evaporated under reduced pressure to give 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (47.59 g, 100%), m.p. 108°-113°C. The hydrochloride, crystallised from a mixture of 2-propanol, ethanol and ether, had m.p. 195°-200°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17](=[O:18])[C:16]3[CH:19]=[CH:20][C:21]([N+:22]([O-])=O)=[C:14]4[C:15]=3[C:10](=[CH:11][CH:12]=[CH:13]4)[C:9]2=[O:25])[CH2:4][CH2:3]1.CO>O.[Pd]>[NH2:22][C:21]1[CH:20]=[CH:19][C:16]2[C:17](=[O:18])[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:9](=[O:25])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: CN1CCC(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN1CCC(N2C(=O)c3cccc4c(N)ccc(c34)C2=O)CC1
Yield: 79.6 %

Procedure:
A mixture of 2,3-dihydro-2-(1-methyl-piperidin-4-yl)-6-nitro-1H-benz[de]isoquinoline-1,3-dione (11.5 g; 33.9 mmol), prepared as in Example 3, in water (150 mL) and methanol (350 mL) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1.4 g) for 5 hours. The catalyst was removed by filtration and the filtrate concentrated to a small volume. Isopropanol was added and the solution concentrated. Isopropanol was again added to the residue and the solution reconcentrated. The residue was swirled in ethanol and ether and the solid residue collected on a Buechner funnel. Drying under vacuum gave 6-amino-2,3-dihydro-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (9.34 g; 27.0 mmol), m.p 345°-348° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:28][CH3:29])[CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)CCC>C(Cl)Cl>[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: Clc1nccc(-c2cnn3ccccc23)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 125 °C
Yield: 53 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 1.476 g, 6.40 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 1.310 g, 7.04 mmol), p-toluenesulfonic acid monohydrate (1.339 g, 7.04 mmol) and 2-pentanol (45 mL) was heated at 125° C. for 22 h. After cooling, the mixture was filtered. The solid was washed with CH3OH, diethyl ether and then dried on the filter to give a brown solid. The solid was dissolved in CH2Cl2 and this solution was washed with sat. NaHCO3 (×3), water and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in boiling CH3CN and then allowed to cool. The resulting solid was collected by filtration and air dried to give the title compound (1.29 g, 53%) as a brown solid; 1H NMR: 4.03 (3H, s), 7.11 (1H, td), 7.37 (1H, d), 7.41 (1H, d), 7.43-7.48 (1H, m), 8.45 (1H, d), 8.51 (1H, s), 8.58 (1H, d), 8.82-8.84 (2H, m), 9.00 (1H, d); m/z: ES+ MH+ 381.54.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]#[N:33])[CH:14]=2)=[CH:4][N:3]=1.C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:40][N:39]=[N:38][N:33]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
N-(2-Chloro-5-{4-cyano-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (1.6 g, 3.19 mmol), trimethylsilyl azide (0.734 g, 6.37 mmol) and dibutyl(oxo)stannane (0.079 g, 0.319 mmol) were placed in toluene (30 ml) and the mixture heated at 100° C. for 16 h. The mixture was stirred at this temperature over the weekend. The mixture was cooled to room temperature and the solvent removed in vacuo. The residue was adsorbed onto florisil and chromatographed on silica (100 g cartridge) eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol to give the title compound (1.3 g).
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@@H:32]([C@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH:52]C(OCC1C=CC=CC=1)=O)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@@H:32]([C@H:37]([C@@H:42]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:43][C:44](=[O:46])[CH3:45])[O:38][C:39](=[O:41])[CH3:40])[O:33][C:34](=[O:36])[CH3:35])[O:28][C:29](=[O:31])[CH3:30])=[O:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]1[NH2:52])[OH:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2,3,4,5,6-Penta-O-acetyl-D-gulonic acid (benzyl 3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide was hydrogenated as described under Ex. 13.B. and gave 2,3,4,5,6-penta-O-acetyl-D-gulonic acid (benzyl 3,4-di-O-acetyl-2-amino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide, [α]+95.0° (c 0.2; dioxan), MS: m/z 741.4 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)=[O:19]
Reactant: Cn1ccnc1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Product: Cn1ccnc1C(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask was placed 1.0 g (12.2 mmol) 1-methylimidazole. Then, 5.1 ml (12.8 mmol) n-butyllithium was added dropwise and the mixture was stirred for 30 minutes. Then, 2.7 g (12.2 mmol) 3-trifluoromethoxybenzoyl chloride was added dropwise. The contents were mixed for 2 hours at -78° C., then allowed to warm to room temperature for an additional 2 hours. The mixture was quenched with water. The product was extracted with ether, dried and purified by flash chromatography (5-10% ethyl acetate/hexanes, silica gel) and was identified as the desired product by spectroscopic analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(I)cc1Cl
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(I)cc1Cl
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.0 g, 86%). δH (CDCl3) 7.79 (1H, d, J 1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J 8.4 Hz).
Reaction SMILES: C(OC(=O)NC1SC[C@@H]2C[C@H](CO)OC[C@]2(C2C=CC=CC=2F)N=1)(C)(C)C.[C:28]([O:32][C:33](=[O:55])[NH:34][C:35]1[S:36][CH2:37][C@@H:38]2[CH2:44][C@H:43]([CH2:45][F:46])[O:42][CH2:41][C@:39]2([C:47]2[CH:52]=[CH:51][C:50](F)=[CH:49][C:48]=2[F:54])[N:40]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:55])[NH:34][C:35]1[S:36][CH2:37][C@@H:38]2[CH2:44][C@H:43]([CH2:45][F:46])[O:42][CH2:41][C@:39]2([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])[N:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Agent: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CF)C[C@H]2CS1

Procedure:
Compound C26 was prepared from tert-butyl[(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C18) according to the general procedure for the synthesis of tert-butyl[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C25) in Example 4, except that no chromatography was carried out on the crude product. Yield: 40 mg, 0.10 mmol, 100%. LCMS m/z 397.4 (M−1).
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH3:12])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(S)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(SC)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Methyl iodide (14.67 ml, 0.235 mol) was added dropwise to a solution of 3-methoxy-benzenethiol (30 g, 0.214 mol) and potassium carbonate (29.6 g, 0.214 mol) in acetone (400 ml) under nitrogen at 3° C. The reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (300 ml) and the aqueous layer was extracted with diethylether (3×200 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87 g) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (22%).
Reaction SMILES: OC1C=C([NH:8][C:9]2[N:14]=[C:13]([NH:15]C3C=CC=C(O)C=3)[C:12]([F:23])=[CH:11][N:10]=2)C=CC=1.ClC1N=C(Cl)C(F)=CN=1.C(OC1C=CC(N)=CC=1)(C)C>>[F:23][C:12]1[C:13]([NH2:15])=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: CC(C)Oc1ccc(N)cc1
Agent: Fc1cnc(Cl)nc1Cl
Product: Nc1ncc(F)c(N)n1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-isopropoxyaniline were reacted to yield N2,N4-bis(4-isopropoxy)phenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.89 (bs, 1H), 7.47 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=9.0 Hz), 6.87 (d, 2H, J=9.0 Hz), 6.83 (d, 2H, J=8.7 Hz); LCMS: ret. time: 27.51 min.; purity: 98%; MS (m/e): 397 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[C:25]1(O)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:33]1([O:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)[C:34]2[CH2:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3cccc4c3CCCC4)c3ccccc23)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.302 mmol) was dissolved in THF (6 mL). 5,6,7,8-Tetrahydronaphthalen-1-ol (0.067 g, 0.454 mmol) was added, and after 25 min di-tert-butyl azodicarboxylate (0.105 g, 0.454 mmol) was added. The reaction mixture was stirred at 40° C. for 5 h. The solvent was removed in vacuo. The crude product was flash chromatographed (9:1 hexane:EtOAc) and tert-butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate was obtained in 22% yield. tert-Butyl 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.028 g, 0.061 mmol) was dissolved in EtOAc (5 mL). 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at rt under N2 for 20 h. The solvent, was removed in vacuo. The crude product was dissolved in EtOAc (2 mL) and Et2O (3 mL) was added dropwise. The precipitate was collected by filtration, wash with Et2O and dried in vacuo at reduced pressure to yield 6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride in 73% yield. 1H NMR (400 MHz, CD3OD) δ 1.66-1.72, 2.35-2.39, 2.65-2.72, 3.20-3.23, 3.36-3.50, 4.23-4.28, 4.61-4.64, 6.51, 6.63, 6.93, 7.10, 7.18, 7.44, 7.50; MS (ESI+) for C24H28N2O m/z 361.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([Br:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.C(=O)([O-])[O-].[CH2:23](I)[CH3:24]>CN(C=O)C>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:18])[N:8]([CH2:23][CH3:24])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]2=[O:16]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)c(Br)cc2c1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Reaction time: 10 h

Procedure:
A mixture of the above ester (7.5 g), pottasium carbonate (7.8 g), ethyl iodide (9.0 ml) and DMF (100 ml was stirred at 90°-110° C. for 10 hours and evaporated. The residue was extracted with chloroform, the chloroform layer was washed with water, and dried. The solvent was evaporated. The residue was added to a solution of sodium hydroxide (4.2 g) and water (100 ml) and refluxed for 30 minutes. The alkaline solution was acidified with concentrated hydrochloric acid and the precipitate was filtered. The precipitate was washed with water, dried, and recrystallized from DMF to give 6-bromo-7-chloro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (6.9 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[N:1]1[C:10]2[C:5](=[C:6]3[C:14](=[O:15])[O:16][C:11](=[O:13])[C:7]3=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c1ccc1ncccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of 5,6-quinolinedicarboxylic acid and acetic anhydride is stirred for 2 hours at reflux temperature, cooled to 0° C. and filtered. The filter cake is dried to give the title product as yellow needles (1.50 g, 82.4%) mp 247°-50° C., identified by H1NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[C:6]2[C:16]1[N:28]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=1.[CH3:39][NH:40][CH3:41]>CN(C=O)C>[CH3:39][N:40]([CH3:41])[CH2:15][CH:13]([OH:14])[CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:16]2[N:28]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:19]3=[N:20][CH:21]=[C:22]4[CH:26]=[N:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[CH:7]1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC1CO1
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2CC(O)CN(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.8 %

Procedure:
In a flask, a mixture of 7-(5-methoxy-1-(oxiran-2-ylmethyl)-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.212 mmol) in DMF (5 mL) and dimethylamine (0.054 mL, 1.061 mmol) was stirred for about 17 h at rt. Additional dimethylamine (0.054 mL, 1.061 mmol) was added and the mixture was heated to about 50° C. for about 5 h, then at rt for about 17 h. The mixture was concentrated in vacuo to provide 1-(dimethylamino)-3-(5-methoxy-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-1-yl)propan-2-ol (0.120 g, 99%): LC/MS (Table 2, Method c) Rt=1.29 min; MS m/z 573 (M+H)+.