Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][O:28][CH2:29][C:30]#[C:31][CH2:32][CH2:33]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:33][CH2:32][C:31]#[C:30][CH2:29][O:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCC#CCOCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCC#CCOCCc1ccccc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of triphenylphosphine (5.25 g) in dry DCM (15 ml) was added to a solution of the product of step (ii) (3.9 g) and carbon tetrabromide (6.63 g) in dry DCM (25 ml) at 0° over 10 min. The yellow solution was stirred at 0° for 30 min, evaporated onto silica (Merck 9385) and purified by FCC eluting with H→H-ER (3:1) to give the title compound as a colourless oil (2.7 g). T.l.c. (H-ER 2:1) Rf 0.69.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccc(F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of rac-1-(4-Fluoro-phenyl)-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (850 mg, 2.54 mmol) in THF (15 ml) was treated with 1M LHMDS in THF (3.30 ml, 3.30 mmol) followed by the addition of iodomethane (0.238 ml, 3.81 mmol). The solution was stirred at RT. After 4 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow oil;
Reaction SMILES: [F:1][C:2]1[C:3]2[N:11]([C@H:12]3[C@H:19]4[C@H:15]([O:16]C(C)(C)[O:18]4)[CH2:14][CH:13]3[F:22])[CH:10]=[N:9][C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[ClH:23]>CO>[NH2:8][C:5]1[C:4]2[N:9]=[CH:10][N:11]([C@@H:12]3[CH:13]([F:22])[CH2:14][C@@H:15]([OH:16])[C@H:19]3[OH:18])[C:3]=2[C:2]([F:1])=[CH:7][N:6]=1.[ClH:23]
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncc(F)c43)C(F)C[C@H]2O1
Agent: Cl
Solvent: CO
Product: Nc1ncc(F)c2c1ncn2[C@@H]1C(F)C[C@@H](O)[C@H]1O

Procedure:
7-fluoro-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (5-12) (30 mg, 0.1 mmol, 1 equiv) was dissolved in MeOH (1 mL) and concentrated HCl (200 uL) was added. After disappearance of the starting material, the mixture was concentrated to afford (1R,2S,3S)-3-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)-4-fluorocyclopentane-1,2-diol (5-13) as a white solid of the bis-HCl salt. 1H NMR (500 MHz, CD3OD): δ 8.59 (s, 1H); 7.82 (d, J=5.0 Hz, 1H); 5.31-5.38 (m, 1 H); 5.28 (d, J=8.5 Hz, 1H); 4.35 (m, 1H); 4.19 (t, J=5.0 Hz, 1H); 2.63 (m, 1H); 2.05 (dd, J=27.5, 16.5 Hz, 1H). LRMS m/z (M+H) 270.9 found, 271.1 required.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])(=[O:14])[CH3:13]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Commercial o-trifluoromethylaniline (13.5 g, 83.9 mmol) was dissolved in acetic anhydride (55 mL, 580.0 mmol) and stirred at room temperature for 1 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (15.7 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([CH3:31])(=[O:30])=[O:29])[C:12]=3[CH3:32])[CH2:9][C:8]([CH3:34])([CH3:33])[C:5]2=[N:6][CH:7]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2(CCC)CC(CCC)=CC(CCC)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:34][C:8]1([CH3:33])[C:5]2=[N:6][CH:7]=[C:2]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:29])=[O:30])[C:12]=2[CH3:32])[CH2:9]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCC1=CC(CCC)=C(c2ccccc2)C(CCC)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Temperature: 105 °C

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-quinoline (42 mg, 0.078 mmol) (described herein), morpholine (14 μL, 0.16 mmol), Pd2dba3 (5.0 mg, 5.4 μmol), 2-(dicyclohexylphosphino)-2,4,6-tri-1-propyl-1,1-biphenyl (5.6 mg, 0.012 mmol), and sodium tert-butoxide (15 mg, 0.155 mmol) in toluene (1.3 mL), and heating at 105° C. for 18 h. Purification afforded 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline as a yellow powder. Compound is rotameric. 1H NMR (400 MHz, chloroform-d) δ ppm 8.15-8.29 (1H, m), 7.84-8.09 (1H, m), 7.77-7.83 (1H, m), 7.69-7.77 (2H, m), 7.55-7.69 (1H, m), 7.43-7.54 (1H, m), 7.31-7.43 (1H, m), 5.86 and 6.10 (1H, m), 4.05 (1H, m), 3.67-3.87 (5H, m), 3.14 (1H, m), 2.90-3.12 (6H, m), 2.00-2.16 (1H, m), 1.92 (2H, s), 1.46-1.68 (6H, m). Mass Spectrum (ESI) m/e=547 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:17][C:10]1[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:7]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Yield: 66.3 %

Procedure:
In 25 ml of ethyl acetate was dissolved 0.35 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-(1,2,4-triazol-1-yl)pyridine, whereto 0.2 g of 10% Pd-C (50% wet) was added. The mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent:chloroform/ethyl acetate 4:1), to give 0.215 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OCC(C)(C)CO2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:22]#[N:23])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC1(C)COB(c2cc(F)cc([N+](=O)[O-])c2)OC1
Reactant: N#Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 2-(3-fluoro-5-nitrophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (15 g, 59 mmol) and 2-bromobenzonitrile (12.4 g, 68.2 mmol) in 1,2-dimethoxyethane (125 ml) and 2M aqueous sodium carbonate (50 ml) was degassed with nitrogen for 30 min then treated with tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.8 mmol). The reaction was then heated at 90° C. for 16 h, cooled to ambient temperature and partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by dry flash chromatography on silica, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (10-40%) afforded 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a cream-coloured solid (10.3 g, 72%): δH (400 MHz, CDCl3) 7.54-7.61 (2H, m), 7.65 (1H, ddd, J 8, 2 and 2), 7.74 (1H, ddd, J 8, 8 and 2), 7.84 (1H, dd, J 8 and 2), 8.03 (1H, ddd, J 8, 8 and 2), 8.22-8.24 (1H, m).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[CH2:33][NH:32][C@H:31]([CH3:34])[CH2:30][N:29]1[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:32]2[CH2:33][C@@H:28]([CH3:27])[N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][C@@H:31]2[CH3:34])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)[C@@H](C)CN1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)[C@@H](C)CN1c1ccc2ccccc2n1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(trans-2,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19]1([CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:16]([C:12]1[CH:11]=[C:10]([CH:3]([NH:2][C:26](=[O:27])[CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:29][CH3:30])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Corresponding to Example 3a, 5.0 g of (1b) were acetylated with addition of 2-phenylbutyryl chloride. A white solid was obtained (yield: 6.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([O:12][CH3:13])[N:8]=[CH:9][C:10]=2[N:11]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:17]2[S:16][C:15]([NH:14][C:2]3[CH:3]=[CH:4][C:5]4[N:6]=[C:7]([O:12][CH3:13])[N:8]=[CH:9][C:10]=4[N:11]=3)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=2)=[CH:28][CH:27]=1)([CH3:31])[CH3:30]
Reactant: COc1ncc2nc(Br)ccc2n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncc2nc(Nc3sc(-c4ccc(C(C)(C)O)cc4)cc3C(N)=O)ccc2n1

Procedure:
The title compound was prepared according to the general procedure in Example 30 (Method B) using 6-bromo-2-methoxypyrido[3,2-d]pyrimidine (48 mg, 0.20 mmol), 2-amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (50 mg, 0.20 mmol), potassium carbonate (31 mg, 0.22 mmol), X-Phos (49 mg, 0.10 mmol), and tris(dibenzylideneacetone)dipalladium (16 mg, 0.02 mmol) as the starting materials.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C1(C)C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:31][C:26]([O:25][CH2:24][CH3:23])=[O:27])[CH:12]=1
Reactant: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 5.74 ml (93.33 mmol) of 0.58M potassium hexamethyldisilazane in toluene is added dropwise 0.66 ml triethyl phosphonoacetate resulting in a yellow gelatinous mixture. This reaction mixture is stirred at room temperature for 25 min, a solution of 0.5 g (1.66 mmol) 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)-octane in 3 ml toluene is added and the mixture is refluxed for 15 h. The reaction mixture is cooled to room temperature, quenched with 5 ml saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The combined organic phase is washed with water and brine, dried, filtered, and concentrated to give a brown oil which is purified by chromatography using 1:1 ethyl acetate/hexane to yield ethyl 3-[3-(3-pyridyl)propyl]-7-(2-tetrahydropyranyloxy)-hept-2-enoate as a mixture of cis and trans isomers; NMR (CDCl3): delta 5.7 (s,1H), 4.2 (q,2H), 1.3 (t,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:27]4[O:28][CH2:29][CH2:30][O:31][C:26]=4[CH:25]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc2c(c1)OCCO2)c1ccc(Cl)cc1
Yield: 61 %

Procedure:
A solution of 4-Chloro-N-(3-chloro-quinoxalin-2-yl)-benzenesulfonamide (354 mg, 1 mmol) in xylenes (20 mL) was treated with 6-amino-1,4-benzodioxane (2 mmol, 246 μL), and the reaction mixture was refluxed under N2 for 5 h. Removal of the solvent in vacuo gave the desired product which was further purified by column chromatography (hexanes/EtOAc 9:1) to give yellow crystals. MP=257-258° C., Yield 61%, TLC-Rf=0.3 (hexanes/EtOAc 3:1), HPLC/MS: [M+H]+ m/z 469. 1H NMR (CDCl3, 600 MHz): δ 4.31 (m, 2H), 6.88 (d, J=9.0 Hz, 1H), 7.15 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.29 (dd, J=1.2 Hz, 1H), 7.36 (td, J=7.8 Hz, 1.2 Hz, 1H), 7.42 (td, J=7.8 Hz, 1.2 Hz, 1H), 7.53 (d, J=9 Hz, 2H), 7.70 (m, 2H), 7.98 (d, J=8.4 Hz, 2H), 8.19 (br.s, 1H), 11.88 (br.s, 1H). 13C NMR (CDCl3, 150 MHz): δ 64.34, 64.53, 109.36, 113.54, 116.18, 117.28, 124.16, 125.87, 126.60, 126.81, 127.89, 129.38, 131.99, 134.18, 139.41, 140.14, 140.28, 141.24, 143.43, 144.08. HRMS: Calcd. for C22H18ClN4O4S [M+H]+ m/z 469.0732, Observed 469.0704.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]12[CH2:19][C:15]([CH2:20]O)([CH2:16][CH2:17][CH2:18]1)[CH2:14][CH2:13][CH2:12]2.Cl.[NH2:23][OH:24].C[O-].[Na+].CO.C[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[N:11]12[CH2:19][C:15]([CH:20]=[N:23][OH:24])([CH2:16][CH2:17][CH2:18]1)[CH2:14][CH2:13][CH2:12]2
Reactant: NO
Reactant: OCC12CCCN(CCC1)C2
Agent: C[O-]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ON=CC12CCCN(CCC1)C2
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A cooled (-65° C.) solution of oxalyl chloride (5.3 mL, 60 mmol)in anhydrous methylene chloride (100 mL) under nitrogen was treated dropwise with anhydrous dimethylsulfoxide (0.60 g, 120 mmol) in methylene chloride (30 mL) at a rate to keep the reaction temperature below -60° C. After 30 minutes at -65° C., a solution of 1-azabicyclo[ 3.3.1]nonane-5-methanol (6.21 g, 40 mmol) in methylene chloride (30 mL) was added dropwise at a rate to keep the reaction temperature below -55° C., and the mixture was stirred at -55±5° C. for one hour. Triethylamine (40 mL) was added the temperature was kept below -50° C.), then the mixture was allowed to warm to room temperature over one hour and diluted with methylene chloride (200 mL). The organic solution was washed with water (200 mL), saturated aqueous sodium carbonate (200 mL), and brine (200 mL), and each aqueous extract was backwashed with methylene chloride. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and taken up in methanol (100 mL), then treated with hydroxylamine hydrochloride (3.5 g, 50 mmol) and 25% sodium methoxide/methanol (1.8 g). After 2 hours at room temperature, additional 25% sodium methoxide (9.0 g) was added, and the mixture was warmed to 45° C. for 30 minutes, then partially concentrated and diluted with methylene chloride (150 mL). The organic solution was washed with saturated aqueous sodium carbonate (100 mL), and the aqueous layer was salted with potassium carbonate and extracted with methylene chloride (3×100 mL). The combined organic solution was dried (Na2SO4), concentrated in vacuo, and recrystallized from acetonitrile (2 crops) to afford 4.03 g (60%) of colorless crystals; mp 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1[C:42]([C@@H:51]([NH:61][C:62](=[O:80])CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=[N:43][C:44](S(C)(=O)=O)=NC=1.NCCN1CCNC1=O>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:44][N:43]2[CH2:42][CH2:51][NH:61][C:62]2=[O:80])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: NCCN1CCNC1=O
Product: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCN2CCNC2=O)ncc1Br

Procedure:
The title compound (22A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and 1-(2-aminoethyl)imidazolidin-2-one. MS (m/z) 725.15 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
12 drops of dimethylformamide was added to a solution of 3.0 g (18.9 mmol) of 2-chloropyrimidine-4-carboxylic acid in 60 ml of thionyl chloride. The reaction was then refluxed for 6 hours. After cooling to room temperature, excess thionyl chloride was removed on a rotary evaporator and the residue distilled (boiling point approximately 100° C./1 mbar). 2.95 g of product, corresponding to a yield of 88 percent relative to the 2-chloropyrimidine-4-carboxylic acid used, which crystallized in the receiving flask, was obtained. The melting point of the product was 52.2° to 53.1° C. Other data for the product was:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][Cl:3])=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: OCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml (10 mmol) thionylchloride in 5.5 ml of toluene is cooled to −10° C. Solid {4-[4-(3-chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol is added and the suspension stirred at 0° C. for 2 h and then at RT for 17 h. The solid is filtered off, washed with toluene and suspended in water (3 ml). The mixture is treated with saturated sodium bicarbonate solution (3 ml) and stirred for 10 min. The crystals are collected by filtration washed with water, a small amount of ethanol and ether and dried to give the title compound; m.p. decomposition ˜300° C.; Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.61; MS-ES+: (M+H)+=383.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)C(=O)O)c1
Agent: Br
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(O)c1
Temperature: 100 °C

Procedure:
2-(3-Methoxy-phenyl)-propionic acid (0.1 g, 0.55 mmol) was dissolved in a mixture of hydrogen bromide (2 mL) and acetic acid (2 mL) and heated to 100° C. overnight. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH:26]([CH3:31])[O:27][C:28](=[O:30])[CH:29]=1)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][CH:26]1[C:25]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[C:2]2=[O:1])=[CH:29][C:28](=[O:30])[O:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1OC(=O)C=C1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(=O)C=C1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (232 mg, 0.944 mmol), Xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen and heated at 65° C. for 16 h. After filtration through CELITE® the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 351.15.