Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30]([O:32]C)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:16]([C:30]([OH:32])=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 14) (59.8 mg, 0.12 mmol) in THF (2 mL) at room temperature under argon was added 2M NaOH (0.18 mL, 0.36 mmol). The reaction mixture was stirred at room temperature overnight. Most of the product was precipitated out. Solvents were removed in vacuo. 10 mL of water and 1 mL of 1 M HCl were added. The product was collected by filtration and further washed with water (3 mL×2). After drying overnight, 56.7 mg (96%) of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid was obtained as a white solid. MS (ESI) 428 (M+H-tBu).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:51])([F:50])[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][N:42]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:11][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:47]([C:45]5[CH:44]=[CH:43][N:42]=[C:41]([C:40]([F:51])([F:39])[F:50])[N:46]=5)=[O:48])[CH2:5][CH2:6]4)[CH2:13]3)[CH:15]=2)=[N:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
Agent: Cl
Product: N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)n3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 2-trifluoromethylpyrimidin-4-carboxylic acid following the procedure described for Example 261, followed by purification with HPLC (method B) provided the title compound. LC-MS: 536.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.93 (brs, 1H), 9.18 (d, 1H), 8.59 (s, 1H), 7.95 (d, 1H), 7.79 (s, 1H), 7.48 (d, 1H), 7.05 (d, 1H), 6.91 (d, 2H), 4.00 (m, 1H), 3.55 (d, 2H), 3.40 (d, 2H), 3.35 (m, 1H), 3.30 (s 2H), 3.23 (m, 2H), 3.11 (m, 1H), 2.58 (m, 1H), 1.80-1.52 (m, 2H), 1.22 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:53]([O:57][CH:58]=[CH2:59])[CH2:54][CH2:55][CH3:56]>C(O)CO.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([O:57][C:58]([C:2]1[C:3]([F:23])=[C:4]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:59])[CH2:54][CH2:55][CH3:56]
Reactant: C=COCCCC
Reactant: COCN(c1cccc(Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: OCCO
Solvent: ClCCl
Product: C=C(OCCCC)c1cccc(N(COC)S(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 6.15 g (15 mmol) of N-(3-bromo-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 35 mL of ethylenglycol in a flask equipped with a rubber septum, through which nitrogen is fluxed by a needle, 37.5 mg (0.15 mmol) of palladium acetate, 129 mg (0.30 mmol) of DPPP, 5.4 mL (37.5 mmol) of TEA and 5.9 mL (45 mmol) of n-butylvinylether were added consecutively. The mixture was heated at 120° C. under stirring for 6 h and then diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated, giving N-[3-(1-butoxyethenyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide as a brown oil. The latter, without any further purification, was dissolved in 65 mL of 1,4-dioxane and 11 mL of 1N HCl were added to the resulting solution. After 1 h under stirring at r.t. the reaction was complete. The solvent was then removed, the residue re-dissolved with DCM and washed with aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated. After trituration with diethylether 4.82 g (86%) of the title compound were collected by filtration.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([Br:11])[CH2:9][CH2:8][C:7]2[N:6]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[Cl:21][CH2:22][CH:23](O)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:21][CH2:22][CH:23]1[CH2:24][O:25][C:2]2([CH:10]([Br:11])[CH2:9][CH2:8][C:7]3[N:6]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]2=3)[O:1]1
Reactant: OCC(O)CCl
Reactant: O=C1c2ccn(S(=O)(=O)c3ccccc3)c2CCC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c1CCC(Br)C21OCC(CCl)O1
Yield: 97 %

Procedure:
In a three necked flask equipped with a thermometer, a stirrer and a reflux condenser having Widmer-type water trap filled with Molecular Sieves are placed 4-oxo-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole (100 parts), 3-chloro-1,2-propanediol (311 parts), p-toluene-sulfonic acid monohydrate (3 parts) and roluene (4500 parts), and the mixture is refluxed for 7 hours 20 minutes while drying the refluxing azeotropic mixture. After cooling, the reaction mixtue is adjusted to pH 9 with 2.5N aqueous sodium hydroxide with stirring, and the formed toluene layer is separated. The water layer is washed with benzene (200 parts). Toluene layer and benzene washing are combined, washed twice with water (500 parts) and dried over anhydrous sodium sulfate (500 parts). The drying agent is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue (143 parts) is dissolved in benzene (300 parts), stirred with active charcoal (50 parts) for 30 minutes and filtered through a filter-bed of siliceous earth. The filtrate is concentrated under reduced pressure, and stirring of resulted residue with a small amount of ether and hexane affords amorphous powder. This is collected by filtration, washed with a mixture of ether and hexane, and dried to give 4'-chloromethyl-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane diastereomer mixture (122 parts) in 97% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH:13]C(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]#[N:13])[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)(C)NC(=O)C1CCN(C(=O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1CCN(C(=O)CCl)CC1
Temperature: 55 °C
Yield: 97 %

Procedure:
To a solution of 1-(2-chloroacetyl)-N-(1,1-dimethylethyl)-4-piperidinecarboxamide (26.1 g, 0.10 mol) in N,N-dimethylformamide (35 mL) was added phosphorus oxychloride (18.8 g, 0.123 mol) dropwise over 30 minutes while allowing the temperature of the reaction mixture to rise to 37° C. The reaction mixture was heated at 55° C. for 1 h and then was slowly added to water (about 150 g) cooled with ice to maintain a temperature of about 10° C. The pH of the reaction mixture was adjusted to 5.5 with 50% NaOH aqueous solution. The mixture was extracted with dichloromethane (4×100 mL), and the combined extract was concentrated under reduced pressure to give 18.1 g of the title compound as a solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [OH:1][C@H:2]([CH3:17])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=2[N+:13]([O-])=O)[CH:6]=[N:5]1>CO.[Pd]>[NH2:13][C:11]1[C:10]([OH:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][C@H:2]([OH:1])[CH3:17])[N:5]=[CH:6]2
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)Cn1ncc2ccc(O)c(N)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product from Step B (1.84 g, 7.76 mmol) in methanol (20 mL) was added palladium-on-carbon (100 mg) and this mixture was stirred under a hydrogen atmosphere at room temperature for 4 h. The reaction mixture was filtered (avoiding air) and evaporated to a colorless oil: LC/MS m/z 208. This oil was immediately carried into the next step.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[C:35]([F:44])[CH:34]=1>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[C:35]([F:44])[CH:34]=2)=[O:13])=[CH:7][C:6]=1[O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1OCC1CC1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1OCC1CC1
Yield: 78.6 %

Procedure:
[4-tert-Butyl-3-(cyclopropylmethoxy)phenoxy]acetic acid (139 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (89 mg, 0.6 mmol), triethylamine (0.2 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (140 mg, 0.6 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1) to furnish 188 mg (78% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][NH2:30]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCCc1ccccn1
Product: O=C(NCCCc1ccccn1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-(2-pyridyl)propan-1-amine (20.0 mg, 0.12 mmol). The title compound was obtained as a solid (14.5 mg, 26% yield). MS m/z: 469.01, 471.01 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].CS(O[CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:6]=2[C:5](=[O:31])[N:4]([CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])[C:3]1=[O:32]
Reactant: CS(=O)(=O)OCCC(F)(F)F
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCC(F)(F)F)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.06 mmol, intermediate 12, step 2) in DMF (6 mL) was added 3,3,3-trifluoropropyl methanesulfonate (305 mg, 1.59 mmol) followed by potassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and extracted with brine. The organic phase was dried and concentrated to give 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min; LCMS MH+ 569.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:4]([Cl:32])[CH:3]=1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[C:4]([Cl:32])[CH:3]=1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1
Reactant: OC1CCNCC1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 623.3 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:11][N:10]=[C:9](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)(=O)=O.[NH3:30]>O1CCOCC1>[C:22]1(/[CH:21]=[CH:20]/[C:9]2[N:8]=[C:7]([NH2:30])[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N
Reactant: O=S(=O)(Oc1nc(/C=C/c2ccccc2)ncc1OC1CCCCO1)C(F)(F)F
Solvent: C1COCCO1
Product: Nc1nc(/C=C/c2ccccc2)ncc1OC1CCCCO1
Yield: 63 %

Procedure:
Crude 2-[(E)-2-phenylethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-4-pyrimidinyl trifluoromethanesulfonate (6.8 mmol) was reacted with a 0.5M solution of ammonia in 1,4-dioxane (136 mL) in a pressure bottle at 60° C. for 24 h. The reaction was concentrated under vacuum, the residue was taken up in DCM and washed with water, saturated aq. NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica gel) using a MeOH/DCM gradient to yield the desired compound as a tan solid (1.28 g, 63% for two steps).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24]>CO>[ClH:24].[ClH:24].[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 50 mL 3-necked round bottom flask fitted with a thermometer, was charged with 30 mL of methanol (HPLC grade), and tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (1.71 g, 5.37 mmol) was then added over a period of 5 minutes. The resulting brown suspension was stirred at room temperature for 30 minutes. Hydrogen chloride gas (Reagent Plus, steel cylinder, Aldrich) was carefully bubbled into the reaction mixture, resulting in a dark brown solution (Note: the temperatures of the reaction mixture rises to 38° C.). The flow of gas was stopped when the reaction mixture was saturated with hydrogen chloride. After 20 minutes a solid precipitated out of solution, and the resulting slurry was cooled to room temperature. The progress of the reaction was monitored by LCMS. The reaction was complete in 6 hours. The reaction mixture was diluted with isopropyl acetate (25 mL) and stirred for an additional 30 minutes; the solids were then collected by vacuum filtration. The resulting brown solid was washed with isopropyl acetate (5 mL), and dried to constant weight to give 1.32 g (84% yield) of 1-piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 11.77 (broad s, 1H), 8.32 (broad s, 3H), 7.95 (d, 1H), 7.93 (s, 1H), 7.06 (dd, 1H), 4.60 (m, 1H), 3.39 (d, 2H), 3.07 (q, 2H), 3.65 (dq, 2H), 1.86 (d, 2H). MS (EI) for C11H14N4; 219 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([OH:24])=O.[N:28]1([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([N:31]1[CH2:30][CH2:29][N:28]([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH2:33][CH2:32]1)=[O:24]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 9 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3-Chloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (51 mg) in 9% yield as colorless oil. MS m/e=565.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:16]=1)[CH2:9][C:8]2([CH3:23])[CH3:22])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(C)CC3)c1)N2
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.94 g, 5 mmol), 1-methyl-piperazine (2.2 mL, 20 mmol), copper(I) iodide (0.38 g, 2 mmol), N,N-dimethylglycine hydrochloride (0.42 g, 3 mmol), and potassium carbonate (2.07 g, 15 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL×2), washed with saturated aqueous ammonium chloride solution (20 mL×3) and brine (20 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (0.61 g, 30%) as a yellow solid: MS (ESI) M+1=407.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (26 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:16]4[CH2:21][N:20]([C:22]([O:24][C:25](C)(C)C)=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:38]1N=C(N2CCOC[C@@H]2C)C2CN(C(OC)=O)CC=2N=1.C1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=C(F)C=2)=O)CC1>>[CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][C@@H:34]4[CH3:38])[C:16]4[CH2:21][N:20]([C:22]([O:24][CH3:25])=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 10 %

Procedure:
Method as described for tert-Butyl 2-(4-(3-(cyclopropylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 143) using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) (193 mg, 0.5 mmol) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (182 mg, 0.57 mmol) as starting materials. Reaction mixture was partitioned between EtOAc (50 ml) and water (35 ml), the organic layer passed through a hydrophobic frit and concentrated in vacuo to leave a brown solid. The solid was purified by prep. HPLC at low pH to afford a colourless solid (22 mg, 10%).