Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (10 g, 29.2 mmol) and 2-amino-4,6-difluorobenzoic acid (source: Buttpark Ltd.) (5.06 g, 29.2 mmol) in iPrOH (250 ml) and DIPEA (25.5 ml, 146 mmol) was heated at 95° C. overnight, then distilled 180 mL of solvent off over 4 h, then heated for another 2 h. After allowing to cool to rt, the reaction mixture was diluted with EtOAc (300 mL), washed with a 1N HCl solution (400 mL), a saturated NaHCO3 solution (200 mL), a saturated NaCl solution (200 mL). The organic layer was diluted with Et2O (200 mL). The resulting slurry was filtered, the solid dried in vacuum oven overnight at 80° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzoic acid as a pale yellow solid (5.3 g, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3H), 6.60-6.78 (m, 2H), 7.48 (d, J=8.06 Hz, 2H), 7.77 (d, J=3.85 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.23-8.36 (m, 1H); ESIMS (M+H)+=478.94.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:9]=1)([CH3:7])([CH3:6])[CH3:5].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[C:4]([C:8]1[C:12]([CH2:13][NH:3][CH2:1][CH3:2])=[CH:11][N:10]([CH2:15][C:16]([NH:18][C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26][CH2:27][C:21]=3[C:20]=2[C:28]([NH2:30])=[O:29])=[O:17])[N:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCNCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 8 %

Procedure:
Ethylamine (175 mg, 0.205 mL, 3.89 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (151 mg, 0.389 mmol) and acetic acid (0.5 mL) in DMF (2.5 mL). Sodium triacetoxyborohydride (824 mg, 3.89 mmol) was added and the mixture stirred for 17 h. Water (300 μL) was added and the reaction stirred for 30 min. The reaction was filtered and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and the product eluted with 2M NH3 in MeOH. Volatiles were blown down to give 2-(2-(3-tert-butyl-4-((ethylamino)methyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (13 mg, 0.031 mmol, 8%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:31][CH3:32])[CH2:20][O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(Cl)(C)(=O)=O.C(N(CC)CC)C.[Br-:45].[Li+]>O1CCCC1.O>[Br:45][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][CH2:20][CH:19]([O:31][CH3:32])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:24]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CBr)c1)OC
Reaction time: 2 h

Procedure:
To a solution of 4 g of 3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzenemethanol and 3.05 g of mesyl chloride in 40 ml of tetrahydrofuran at 0° C. was added over 20 minutes a solution of 2.69 g of triethylamine in 10 ml of tetrahydrofuran. A 7.71 g portion of lithium bromide was added and the mixture was stirred for 2 hours, diluted with water and filtered. The filtrate was poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried and evaporated, giving 4.5 g of 1-(bromomethyl)-3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzene as an oil.
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([N:28]2[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]2)=[N:10][CH:11]=[C:12]([CH:27]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].[NH:34]1[CH:38]=[CH:37][C:36](B(O)O)=[N:35]1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCO.O>[OH:33][C@@H:30]1[CH2:31][CH2:32][N:28]([C:9]2[C:8]([C:38]3[CH:37]=[CH:36][NH:35][N:34]=3)=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:10]=2)[CH2:29]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc[nH]n2)c1

Procedure:
A mixture of DME (570 μL), water (163 μL) and EtOH (81 μL) was added to a mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 60 mg, 0.134 mmol), (1H-pyrazol-3-yl)boronic acid (45.1 mg, 0.403 mmol) Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol), Na2CO3 (42.8 mg, 0.403 mmol) in a MW vial. The vial was sealed, evacuated/purged 3 times with argon and the RM was subjected to MW irradiation at 120° C. for 10 min. Additional (1H-pyrazol-3-yl)boronic acid (45.1 mg, 0.403 mmol) was added and the RM was subjected to MW irradiation at 120° C. for 30 min, diluted with THF (1 mL) and treated with Si-Thiol (Silicycle 1.27 mmol/g, 52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 15% for 0.2 min then 15% to 45% in 14 min) to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[N:3][CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.32 g, 1.13 mmol), 2-methoxybenzeneboronic acid (0.19 g, 1.25 mmol), tetrakis(triphenylphosphine)palladium (65.5 mg, 0.057 mmol), and 2.0M sodium carbonate (3.0 mL, 6.00 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.93 (1H, d, J=2.0 Hz), 8.37 (1H, d, J=2.0 Hz), 7.66 (1H, dd, J=7.5, 1.7 Hz), 7.52 (1H, m), 7.16 (1H, td, J=7.5, 1.0 Hz), 6.92 (1H, dd, J=8.3, 0.7 Hz), 3.72 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.25 g, 1.0 mmol) in DMF (5 mL) was added potassium carbonate (0.14 g, 1.0 mmol), followed by iodomethane (0.42 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by addition of brine (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/4) on silica gel to give the title compound as a white solid. (253 mg, Yield: 94%). MS (ESI) m/z=269 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>O1CCOCC1>[CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=[S:27])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)CC(C)c1ccccc1NC(=O)c1cn(C)cc1C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)CC(C)c1ccccc1NC(=S)c1cn(C)cc1C(F)(F)F
Temperature: 72.5 °C

Procedure:
In a sulfonation flask a mixture of 0.6 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid[2-(1,3-dimethylbutyl)phenyl]amide, 0.45 g P2S5 and 30 ml dioxane is heated at 70-75° C. for 3 hours. After filtration, the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and ethylacetate is removed in a water jet vacuum. The crude material is purified by column chromatography over silica gel (eluant:ethylacetate/n-hexane=1:1). Yield: 0.53 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carbothioic acid[2-(1,3-dimethylbutyl)phenyl]amide in the form of a reddish resin (1H-NMR).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:43]=1[CH2:44][N:45]([CH2:53]OC)[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:40][O:41][C:42]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:43]=1[CH2:44][N:45]([CH2:53][C@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:23])[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(Cc1ccc(OC)cc1OC)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)cc2)C(=O)OC(C)(C)C)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
(R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (3.00 g, 9.10 mmol) was dissolved in DCM (91 mL) and cooled to −78° C. A 1M toluene solution of TiCl4 (11.4 mL, 11.4 mmol) was added to the solution followed by DIEA (1.66 mL, 9.55 mmol) to afford a dark purple reaction. This was allowed to stir for 15 minutes before the tert-butyl 2,4-dimethoxybenzyl(methoxymethyl)carbamate (3.40 g, 10.9 mmol) was added as a solution in DCM (10 mL) dropwise. The reaction was allowed to stir for 15 minutes at −78° C., then allowed to warm to −18° C. in a brine-ice bath for one hour. This reaction was allowed to warm slowly to 0° C. over a 2.5 hour period. The reaction was then quenched with the addition of saturated NH4Cl solution (100 mL). The layers were separated, and the organic layers was extracted once with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. The residue was purified by chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate) to afford the pure material as a colorless oil tert-butyl 2,4-dimethoxybenzyl((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate (4.07 g, 73.5% yield). This tert-butyl 2,4-dimethoxybenzyl((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate (680 mg, 1.12 mmol) was dissolved in DCM (10.6 mL) and water (560 uL; 19:1 DCM:water) at ambient temperature. The solution was treated with DDQ (380 mg, 1.67 mmol), and the reaction was allowed to stir for one day to afford reaction completion by TLC and LCMS analysis. The reaction was diluted with DCM and washed twice with half saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow-orange oil. The residue was purified by chromatography (silica gel eluted with 9:1 hexanes:ethyl acetate) to afford a mixture of the aldehyde by-product and tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (not separable) as a pale-yellow oil (729 mg combined mass). LC/MS (APCI+) m/z 359.1 [M−BOC+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([CH2:29][N:28]([CH3:45])[CH3:27])=[CH:31][CH:32]=4)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[O:15])[C:5]=3[CH:6]=[N:7]2)[CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CC2)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c2cnn3C2CC2)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.070 g, 0.169 mmol), N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.060 g, 0.202 mmol), and potassium phosphate (tribasic) (0.107 g, 0.506 mmol) were added 1,4-dioxane (2.0 mL) and water (0.5 mL). The suspension was stirred with degassing under N2 for 10 min. (emulsion), and then PdCl2(dppf)-CH2Cl2 adduct (0.021 g, 0.025 mmol) was added. The contents were sealed and heated at 100° C. (heat block) for 2 h. After cooling to RT, the reaction mixture was diluted with EtOAc. Silica gel was added the mixture was concentrated in vacuo to dryness. The contents were purified by silica gel chromatography (dry loaded, eluent: 8-95% gradient chloroform (containing 10% 2M Ammonia in Methanol) and DCM). The collected product was concentrated from MTBE and dried in a vacuum oven for 2 h. The title compound was collected as a white solid (67 mg, 81%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.20 (m, 4H), 2.12 (s, 3H), 2.15-2.24 (m, 9H), 3.44 (s, 2H), 3.87 (t, J=5.31 Hz, 1H), 4.38 (d, J=4.80 Hz, 2H), 5.88 (s, 1H), 7.42 (m, J=8.34 Hz, 2H), 7.80 (m, J=8.08 Hz, 2H), 7.90 (s, 1H), 8.04 (s, 1H), 8.31 (s, 1H), 8.67 (t, J=4.93 Hz, 1H), 11.53 (s, 1H); LC-MS (ES) m/z=470.3 [M+H].
Reaction SMILES: C(OC(N1CCC(NC2N=CC(OCC#N)=CN=2)CC1)=O)(C)(C)C.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[N:44]=[CH:43][C:42]([OH:45])=[CH:41][N:40]=2)[CH2:34][CH2:33]1)=O)(C)(C)C.CC1(C)[O:51][CH:50]([CH2:52]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:49][O:48]1.C(=O)([O-])[O-].[K+].[K+].Cl.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>CN(C=O)C.O1CCOCC1.C(O)C>[NH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:39]2[N:40]=[CH:41][C:42]([O:45][CH2:52][CH:50]([OH:51])[CH2:49][OH:48])=[CH:43][N:44]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCO
Product: OCC(O)COc1cnc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the synthesis of 4-(5-cyanomethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C32/step 1) from 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C31/step 2) by reaction with rac-toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (commercially available) and potassium carbonate in DMF at rt for 48 h, followed by BOC and isopropylidene cleavage with 4 M HCl in dioxane and ethanol at 60° C. in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3) and subsequent ion exchange chromatography on Q-Sepharose Fast Flow. MS (ISP): 269.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[S:18][C:11]=12)[NH2:5]
Reactant: CN1CCNCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.518 mmol), 1-methyl piperazine (0.172 ml, 1.55 mmol), copper(I) iodide (29.59 mg, 0.155 mmol), (S) -pyrrolidine-2-carboxylic acid (17.89 mg, 0.155 mmol), K2CO3 (357.9 mg, 2.59 mmol) and DMSO (25 mL). The reaction mixture was stirred at 100° C. until the starting material had been consumed (overnight). Then the reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (158.5 mg, 85%). LRMS (APCI pos): >95% purity, 254 nm, m/e 359.3 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.11 (d, 1H), 6.96 (t, 1H), 6.53 (dd, 1H), 6.49 (m, 1H), 6.29 (m, 2H), 3.36 (m, 4H), 2.60 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][CH2:14][C:15]1[NH:24][C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[CH2:6]([O:13][CH2:14][C:15]1[N:24]=[C:23]([Cl:3])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(COCc3ccccc3)[nH]c(=O)c2c1
Solvent: CC#N
Product: COc1ccc2nc(COCc3ccccc3)nc(Cl)c2c1
Reaction time: 1 h
Yield: 69 %

Procedure:
30 ml of phosphorus oxychloride was added to a suspension of 1.50 g (5.06 mmol) of 2-benzyloxymethyl-6-methoxyquinazoline-4(3H)-one in 75 ml of acetonitrile. The obtained mixture was heated under reflux. After one hour, the reaction mixture was distilled under a reduced pressure to remove the solvent and the obtained residue was dissolved in chloroform. The obtained solution was washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 1.10 g of the title compound as a yellow crystal.
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.O=[C:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[F:13][C:12]([F:14])([F:15])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:28]2[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:27]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Reaction time: 16 h
Yield: 109.9 %

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in methanol (5 mL) at room temperature was added benzyl 3-oxopyrrolidine-1-carboxylate (434 mg, 1.98 mmol) followed by sodium triacetoxyborohydride (470 mg, 2.22 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate (906 mg, 88%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.44 (m, 2H), 1.50-1.68 (m, 2H), 1.80-2.00 (m, 2H), 2.10-3.29 (m, 1H), 2.30-2.43 (m, 1H), 2.55-23.05 (m, 3H), 3.15-3.28 (m, 1H), 3.58-4.20 (m, 3H), 4.30-4.50 (m, 1H), 5.09 (s, 2H), 6.70-6.87 (m, 1H), 7.20-7.50 (m, 6H), 7.52 (t, J=8.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 8.09 (s, 1H). MS m/z: 519 (M+1)