Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]([OH:29])[CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[OH:19])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([O:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)[CH2:17][CH2:16][CH:15]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc(C(O)CCC(O)c2cccc([N+](=O)[O-])c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.3 mL, 3.87 mmol) was added dropwise to a cold (0° C.) solution of Example 55B (0.5089 g, 1.531 mmol) and triethylamine (0.65 mL, 4.66 mmol) in THF (10 mL). The reaction was removed from the ice bath and stirred at ambient temperature for 30 minutes. Solvent was removed under vacuum to provide the title compound as a solid that was used without purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]([O:19]O)=[O:18])[CH:11]=1>CCOC(C)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH+:1]1([O-:18])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Cl)c1
Product: [O-][NH+]1C=Cc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to a procedure described in WO2003082289A1. A solution of 1H-pyrrolo[2,3-b]pyridine (10.0 g, 84.6 mmol) in ethyl acetate (846 ml, 84.6 mmol) was cooled to 0° C. To the cold solution was added a solution of mCPBA (103 mmol, 23.1 g, 77% pure) in 53 mL of EtOAc over a period of 1.5 h. Halfway into the reaction, 100 mL of EtOAc was added to the reaction to ease stirring of the thick mixture. The residual mCPBA was washed into the reaction mixture by an additional portion of EtOAc (25 mL). Solid precipitated out of the solution, and the resulting mixture was warmed to rt, and allowed to stir at this temp until the starting azaindole had been consumed as judged by RPLC. After 3 h at rt, the reaction was completed. The reaction mixture was cooled back to 0° C. The resulting slurry was filtered to collect the N-oxide as the meta-chlorobenzoic acid salt. The solid was washed with additional EtOAc and dried under vacuum. The product, 1H-pyrrolo[2,3-b]pyridine 1-oxide salt of mCBA was obtained as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:24].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[C:23]([NH:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]3)[CH2:34]1)[CH2:36]2)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C(=O)C2CCNCC2)ccc1Cl
Yield: 81.5 %

Procedure:
A solution of 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.07 g, Example 76a) in methanol (3 ml) was treated with 4N hydrochloric acid solution in dioxane (1 ml). After 14 h the solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.025 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: CCS(=O)(=O)NC(C)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N(Cc1cccnc1)C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(1-(4-Bromophenyl)ethyl)-N-ethylsulfonylamine (1.25 g, 4.28 mmol), and (0.75 g, 4.6 mmol) of 3-picolyl chloride hydrochloride, and (5.1 g, 37 mmol) of potassium carbonate were dissolved in 40 ml DMF. Additional 3-picolyl chloride hydrochloride (0.75 g, 4.6 mmol) was added after 30 minutes and the mixture stirred 20 h at room temperature. The mixture was diluted with 120 ml ethyl acetate and 60 ml of water and transferred to a separatory funnel. The organic layer was separated and washed twice with water. The organic layer was again separated and dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark oil. The oil was purified by radial chromatography on a 6 micron silica plate eluting with 1 to 4% methanol/dichloromethane to afford after concentration of fractions the title compound. MS calcd. 383.2; MS (M+1) 384.1.
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C(O)C>[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:36])([F:37])[F:22])[CH:25]=4)[CH2:35][CH2:34]3)=[N:9][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CC(C)n1c(CCCl)nc2cc(Br)c3ccccc3c21
Agent: Cl
Solvent: CCO
Product: CC(C)n1c(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-1H-naphth[1,2-d]imidazole hydrochloride with 1-(3-trifluoromethylphenyl)piperazine. M.p. 161°-62° C. (from ethanol).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].CO>N1C=CC=CC=1>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CC=CCC(=O)Nc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: CCC=CC(=O)Nc1ccccc1

Procedure:
52.6 g of pent-3-enanilide, 19.2 g of methanol, 4.75 g of pyridine and 2.05 g of Co2 (CO)8 were reacted analogously to Example 1 for 1.5 hours at 170° C. At a pentenanilide conversion of 58.3 mol %, C6 -dicarboxylic acid methylesteranilides were formed at a selectivity S of conversion of 37.5 mol % (11 =65.3%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[O:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-:22].[Cs+].[Cs+]>O.C(#N)C>[CH:7]1[C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[O:10][C:9]=2[CH:19]=[CH:20][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][OH:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCCC3
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C(CO)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 7.2 %

Procedure:
A mixture of 2-chloro-N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylacetamide (0.115 g, 0.51 mmol) and cesium carbonate (0.34 g) in water (2 mL) and acetonitrile (4 mL) was heated in the microwave for 15 min. The reaction mixture was concentrated and the crude material was purified by HPLC to provide N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl-2-hydroxyacetamide (0.010 g). MS (ESI) m/z 274 ([M+H]+);MS (ESI) m/z 272 ([M−H]−).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][OH:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCCO2
Yield: 60.6 %

Procedure:
A solution of (b) (250 mg, 1.5 mmol) in dichloromethane (5 ml) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: OCc1ccnc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccnc2ccccc12

Procedure:
A solution of methanesulfonyl chloride (4.84 ml) in 20 ml of methylene chloride is slowly added over 20 minutes to a solution of 8.29 g of 4-hydroxymethylquinoline and 11 ml of triethylamine in 200 ml of methylene chloride at 0°. After completion of the reaction at room temperature, the reaction mixture is partitioned between methylene chloride and saturated potassium carbonate solution. The organic layer is dried over sodium sulfate and evaporated to dryness to yield 4-(methanesulfonyloxymethyl)quinoline as an oil. To a solution of 1.62 g of sodium hydride (from 3.24 g of a 50% sodium hydride dispersion in mineral oil) in 100 ml of toluene is added dropwise a solution of 8 ml of diethyl phosphite in 20 ml of toluene. The reaction mixture is heated to 80°,a solution of the above obtained 4-(methanesulfonyloxymethyl)-quinoline in 90 ml of toluene and 10 ml of methylene chloride is added. After 20 minutes a second portion of 1.2 g of sodium hydride is added and the reaction mixture is stirred for an additional 10 minutes. The reaction mixture is then evaporated to dryness, the product is partitioned between water and ethyl acetate. The ethyl acetate extract is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using methanol/methylene chloride (5:95) as eluent to yield 4-(diethylphosphonomethyl)quinoline; Rf =0.3.
Reaction SMILES: [CH:1]([NH2:3])=O.C([O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][C:9]=1[NH2:15])C.C([O-])=O.[NH4+].O>C(OCC)(=O)C>[CH:12]1[CH:11]=[CH:10][C:9]2[N:15]=[CH:1][NH:3][C:7](=[O:6])[C:8]=2[CH:13]=1
Reactant: NC=O
Reactant: CCOC(=O)c1ccc(F)cc1N
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnc2ccccc12
Temperature: 140 °C

Procedure:
The intermediate 4-piperazinyl-7-(2-piperidylethoxy)quinazoline was prepared using the procedures as generally described in Scheme 1 as follows: Step A To the ethanol solution (15 mL) of 2-amino-4-fluorobenzoic acid (840 mg, 5.41 mmol) was added thionyl chloride (1.18 mL, 16.23 mmol) and the resulting suspension was refluxed overnight. The solvent was evaporated to the residue added EtOAc, washed with 10% NaOH solution, dried, filtered and evaporated to afford desired ethyl ester as a solid 981 mg, 82%). MS (ES) 184(M+H) Step B: To the formamide (6 mL) solution of ethyl-2-amino-4-fluorobenzoate (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140° C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H) Step C: To the DMF solution (3 mL) of 1-piperidineethanol (0.689 mL, 5.18 mmol) at 0° C. added sodium hydride (0.518 g, 12.95 mmol) and the mixture was stirred for 30 min. To this cold solution added DMF solution (3 mL) of intermediate quinazolinone (0.284 g, 1.73 mmol, from Step B) and the mixture was heated at 75° C. overnight. The solvent was evaporated and the residue purified by RP-HPLC to afford desired product as a creamy solid (0.459 g, 97%) Step D: A mixture of 7-(2-piperidylethoxy)-4-quinazolinone (0.459 g, 1.68 mmol), from Step C) and POCl3 (5 mL) was heated at 75° C. overnight. After cooling excess POCl3 was removed by evaporation and the residue azeotroped with toluene to afford intermediate, 4-chloro-7-(2-piperidylethoxy)quinazoline (600 mg, 95%) Step E: To the isopropanol solution (10 mL) of 4-chloroquinazoline (0.615 g, 2.11 mmol, from Step D) added piperazine (0.727 g, 8.44 mmol) and heated the reaction for 4 h at 100° C. The solvent was evaporated and the residue purified by RP-HPLC to afford 4-piperazinyl-7-(2-piperidylethoxy)quinazoline as a white solid (0.630 g, 87%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: C1CC(N2CCOCC2)CCN1
Product: CN(C(=O)c1cc2c(s1)-c1cc(N3CCC(N4CCOCC4)CC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and 4-(4-piperidinyl)morpholine were reacted to give 127bp. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.05-7.10 (m, 2H), 6.84-6.93 (m, 3H), 6.74 (m, 1H), 5.05 (s, 2H), 4.00 (m, 4H), 3.63-3.68 (m, 3H), 3.29-3.50 (m, 5H), 3.18 (m, 2H), 3.05 (m, 2H), 2.47 (m, 2H), 2.21 (m, 2H). LCMS (ESI) m/z: 526.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C(OCC)C>O1CCOCC1.O.[Zn]>[NH2:27][C:23]1[CH:22]=[C:21]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[N:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
300 mg (0.72 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine were dissolved in a mixture of 20 ml of dioxane and 4 ml of water and 381 mg (7.2 mmol) of ammonium chloride and 190 mg (2.9 mmol) of metallic zinc were added. The reaction was maintained at 100° C. under stirring for 6 hours. The mixture was then filtered through a celite pad and the solvent removed in vacuo. The residue was partitioned between dichloromethane and water, dried over sodium sulphate and evaporated again, giving, after trituration with diethylether, 260 mg (93%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:40][CH3:41])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(OC)c2)CC1
Yield: 49.2 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 91 mg, 0.33 mmol) and p-toluenesulphonic acid monohydrate (156 mg, 0.81 mmol) were heated at 140° C. in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (89 mg, 50%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[S:7][C:8]3[N:9]=[C:10]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]4[CH2:30][CH3:31])[N:11]=[C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:13]=3[N:14]=2)[CH2:2]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:13]3[N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:4]4)[S:7][C:8]=3[N:9]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A mixture of 2-azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (209 mg, 0.48 mmol), 2-hydroxyisobutyric acid (56 mg, 0.54 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (94 μL, 0.54 mmol) in DCM (5 mL) was allowed to stir at r.t. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-2%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 814 as a white solid (89 mg, 35%). LCMS (method I): RT 3.39 min, [M+H]+ 522.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.28 (2 H, m), 4.62-4.12 (7 H, m), 4.05-3.92 (1 H, m), 3.88 (4 H, t, J=4.76 Hz), 3.45 (1 H, s), 3.43-3.38 (2 H, m), 3.33 (2 H, q, J=7.47 Hz), 3.27-3.21 (1 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]1[C:42]([S:43](Cl)(=[O:45])=[O:44])=[C:41]([CH3:47])[O:40][N:39]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:47])(=[O:45])=[O:44])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice-cold solution of 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 8, (1.0 g, 2.48 mmol) and triethylamine (0.52 mL, 2.73 mmol) in methylene chloride (75 mL) under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonyl chloride (535 mg, 2.73 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with water and the methylene chloride layer was separated, dried (MgSO4), and concentrated to afford 4-({[7-(3,5-dimethyl-isoxazole-4-sulfonyloxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].CCN(C(C)C)C(C)C>CCOC(C)=O>[C:6]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9]1[C@H:14]([O:15][CH3:16])[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:10]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CO[C@@H]1CCNC[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCN(c2ccncc2[N+](=O)[O-])C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
Method 1 was followed using trans(+/−)-3-(bis(tert-butoxycarbonyl)amino)-4-methoxypiperidine (1.0 equiv.), 4-chloro-3-nitropyridine (1.2 equiv.), and DIEA (4.0 equiv.) to give trans(+/−)-N,N-di-BOC-4-methoxy-1-(3-nitropyridin-4-yl)-piperidin-3-amine after column chromatography (EtOAc and hexanes, 50%) in 59% yield for two steps. LCMS (m/z): 453.2 (MH+), LC Rt=3.24 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]([CH2:17][CH2:18][OH:19])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[C:25]([CH3:32])[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31][C:14]([C:13]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:9][C:10](=[O:20])[N:11]([CH2:17][CH2:18][OH:19])[CH:12]=2)=[O:16])=[C:25]([CH3:32])[CH:24]=1
Reactant: O=C(O)C1=CN(CCO)C(=O)NC1c1ccc(F)cc1
Reactant: COc1cc(C)c(N)cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(NC(=O)C2=CN(CCO)C(=O)NC2c2ccc(F)cc2)cc1OC
Yield: 23.5 %

Procedure:
4-(4-Fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(180 mg), 4,5-dimethoxy-2-methyl-phenylamine (86 mg) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 265 mg) were dissolved in 10 mL DMF, followed by 0.2 mL di-iso-propylethyl amine. The mixture was heated at 50° for 72 hours, then cooled, diluted with aqueous pH 2 buffer and ethyl acetate, and the layers separated. The organic layer was washed with saturated sodium bicarbonate and brine, then dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 3% MeOH/DCM. The fraction containing the product was washed with 10% aqueous HCl, and concentrated in vacuo to yield 52 mg of 4-(4-fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(4,5-dimethoxy-2-methyl-phenyl)-amide, MS (M+H)=430.