Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1.N12CCCN=C1CCCCC2>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)([CH:22]3[CH2:23][CH2:24][CH2:25][C:20](=[O:26])[CH2:21]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1Cc1cccc(Cl)c1
Reactant: O=C1C=CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.125 g, 0.49 mmol) (from Example 30b supra), 2-cyclohexen-1-one (0.047 g, 0.49 mmol) (Aldrich), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 g, 2.4 mmol) (Fluka AG) in methanol (20 mL) was heated at 60° C. for 2 hours. After cooling, the mixture was concentrated, diluted with water, extracted with ethyl acetate (2×100 mL). The organic layers were separated, washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-hexanes, 2:3, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3-oxo-cyclohexyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 0.057 g, 30%).
Reaction SMILES: [CH2:1]([CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].C1([NH2:19])CCCCC1>>[NH:19]=[C:11]=[NH:10].[CH2:1]([CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7]
Reactant: NC1CCCCC1
Agent: O=C=NCCCCCCN=C=O
Product: N=C=N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 288 g of HMDI was added 20 g of cyclohexylamine and they were stirred at 100° C. for one hour while nitrogen was bubbled thereinto and subsequently 2.9 g of the carbodiimidization catalyst was added thereto, after which the resulting mixture was subjected to a reaction at 185° C. for 30 hours, to obtain a carbodiimide resulting from HMDI and having terminal urea bonds (degree of polymerization=10).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([Cl:21])=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/C(=O)Cl)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid (4 g, 16.93 mmoles) in toluene (70 ml) and dimethylformamide (10 ml) cooled in an ice bath, oxalyl chloride (4.30 g, 33.87 mmoles) is dropped. The mixture is maintained under stirring at 0° C. for 1 hour then the temperature is let reach the room value and it is left for 2 hours. The solvent is removed at reduced pressure and the raw product is used without further purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C:16]#[C:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
4-Bromobenzaldehyde (370 mg, 2 mmol), phenylacetylene (306 mg, 3 mmol) and tetrakistriphenylphosphine palladium (45 mg) were dissolved in triethylamine (4 ml), and the obtained solution was stirred at 80° C. in argon atmosphere for 24 hours. The solvent was evaporated, and the product was purified by the silica gel column chromatography to obtain 4-(2-phenylethynyl)benzaldehyde (yield: 258 mg, 63%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31]C(=O)OC(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:31][CH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl pyrrolidin-2-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.98 minutes; C21H21Cl2N5O2 (446.34); mass spectrum: (M+H)+=446.2.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1>C(CN)CN.O>[N:5]1[C:4]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:3]=2[C:2]([CH:2]([NH2:7])[CH2:3][CH2:4][NH2:5])=[N:7][CH:6]=1
Reactant: Clc1ncnc2sc3c(c12)CCCC3
Agent: NCCCN
Solvent: O
Product: NCCC(N)c1ncnc2sc3c(c12)CCCC3
Temperature: 25 °C
Yield: 102.8 %

Procedure:
A solution of 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (0.5 g, 2.43 m. mol) in 1,3-diaminepropane (5 ml) was heated at 80° C. for 1 day. It was cooled to room temperature and then diluted with water (50 mL). The clear solution was cooled at 0° C. for overnight. The resulting solid was filtered and dried to get the title compound (0.3 g, 52%) as a brown color solid. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 3.65 (t, 2H), 2.95 (m, 2H), 2.80 (m, 4H), 1.80-2.00 (m, 6H). MS (ESI) m/z: Calculated: 262.37; Observed: 263.1 (M++1).
Reaction SMILES: [CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[NH:26][N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]([O:6]C)=[O:5].O1CCCC1.[OH-].[Li+].Cl>O>[CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[NH:25][N:26]=3)=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1

Procedure:
A 20 mL scintillation vial was charged with the product from Example 26D (12 mg, 0.027 mmol). 80% tetrahydrofuran in water, and lithium hydroxide (2.00 mg, 0.048 mmol) and shaken for 6 hours. After this time the reaction mixture was acidified with 1N HCl, filtered, and evaporated to dryness to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2H), 1.41-1.55 (m, 2 H), 1.74-1.91 (m, 5 H), 2.22-2.31 (m, 2 H), 2.78-2.80 (m, 1 H), 2.96-3.10 (m, 3 H), 3.98 (s, 2 H), 7.05-7.19 (m, 1 H), 7.27-7.45 (m, 2 H), 7.60-7.85 (m, 2 H), 13.98 (s, 1 H); MS (ESI) m/z 424[M+H]+.
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[N:18]=[N:19][C:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][CH2:2][S:3][S:4]3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Product: O=C(CCCCC1CCSS1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use lipoic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (yield 8%). 1H NMR (300 MHz, CDCl3) δ 10.11, 8.37, 7.72, 7.61, 7.53, 7.35, 7.04, 4.08-3.84, 3.70-3.57, 3.56-3.46, 3.33-3.30, 3.17-3.02, 2.59, 2.39, 1.84, 1.78-1.56, 1.51-1.37. 13C NMR (300 MHz, CDCl3): 172.52, 167.57, 157.94, 150.00, 134.42, 132.38, 129.45, 127.79, 127.29, 127.14, 126.93, 126.88, 126.82, 121.92, 116.27, 56.34, 46.47, 45.65, 45.33, 41.25, 40.26, 38.49, 37.05, 34.74, 28.85, 25.14. MS (ES+) m/z 540.1 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.[Na]>C1(C)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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:14][C:15]1[CH:20]=[C:19]([C:10]2[C:11]3[NH:12][C:13]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(I)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: Brc1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Reaction time: 24 h
Yield: 67.5 %

Procedure:
Carbazole (7.3 g, 43.7 mmol), 3-bromoiodobenzene (25 g, 87.3 mmol) and sodium t-buthoxide (8.4 g, 87.3 mmol) is suspended in 150 mL of dry xylene under nitrogen atmosphere. Tris(dibenzylideneacetone)dipalladium (200 mg) and 1,1′-bis(diphenylphosphino)ferrocene (400 mg) are added as one portion and the reaction is heated to reflux and stirred under nitrogen atmosphere for 24 h. After cooling the xylene is evaporated and the residue is subjected to column chromatography on silica gel, providing 3-bromophenyl carbazole (9.5 g, yellow solidified oil).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][N:21]([CH3:33])[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O.CCOC(C)=O.[Pd]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:27]2[CH:28]=[CH:29][C:24]([C:22]([N:21]([CH3:33])[CH3:20])=[O:23])=[CH:25][CH:26]=2)=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)cc1
Temperature: 110 °C
Yield: 56.4 %

Procedure:
5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (150 mg, 0.4715 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (91.00 mg, 0.4715 mmol), sodium carbonate (99.95 mg, 0.9430 mmol) and palladium; triphenylphosphane (54.48 mg, 0.04715 mmol) in a mixture of acetonitrile (1.5 mL) and water (1.5 mL) was heated at 110° C. in the microwave for 30 minutes. The reaction was diluted with water and EtOAc and the layers separated. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petroleum ether) to give the desired product (102.8 mg, 56% Yield). 1H NMR (400.0 MHz, DMSO) d 2.98 (6H, m), 7.55 (2H, m), 7.69-7.71 (3H, m), 7.83 (2H, br s), 8.17-8.20 (4H, m), 9.00 (1H, s) ppm; MS (ES+) 387.13
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (95 mg, 0.33 mmol) to afford the desired product (53 mg, 35%) as a yellow solid. NMR (500 MHz, DMSO-d6) δ 10.50 (d, J=8.0 Hz, 1H), 8.96 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.72 (s, 2H), 4.14-4.06 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.23-2.15 (m, 2H), 2.18 (s, 6H), 2.15-2.10 (m, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.61-1.43 (m, 3H), 1.17-1.01 (m, 5H). ESI MS m/z 500 [C27H31Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.70 min.
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]2[CH3:13].CO.Cl>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]2[CH3:13]
Reactant: CC1C(=O)Nc2ccc(F)cc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1CNc2ccc(F)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 18 mL (18 mmol) of a 1M borane in THF solution was added dropwise to 1.5 g (9.1 mmol) 5-fluoro-3-methyl-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixture was stirred for 2 h at 70° C., cooled to 0° C. and combined with 10 mL methanol and then with 30 mL semi-concentrated hydrochloric acid solution. The reaction mixture was refluxed for 1 h with stirring, cooled and the organic phase was eliminated using the rotary evaporator. The aqueous phase was extracted with ethyl acetate. The aqueous phase was made alkaline with an aqueous 4M sodium hydroxide solution and extracted with dichloromethane. The organic phase was dried on sodium sulphate, filtered off and evaporated down.
Reaction SMILES: [NH:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.I[CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:9]([N:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1)([CH3:11])[CH3:10]
Reactant: O=Cc1cnc[nH]1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cncc1C=O
Temperature: 50 °C
Yield: 95.9 %

Procedure:
A mixture of 1H-imidazole-5-carbaldehyde (800 mg, 8.3 mmol), 2-iodopropane (1.7 g, 10 mmol) and potassium carbonate (1.4 g) in DMF (30 mL) was heated to 50° C. overnight. The mixture was evaporated under reduced pressure, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give 1-isopropyl-1H-imidazole-5-carbaldehyde (1.1 g), LC-MS (ESI) m/z: 139 (M+1)+. This compound (1.1 g, 8.0 mmol) and (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (1.7 g, 7.2 mmol) were added in ethyl propionate (50 mL) then sodium ethoxide was added under 0° C. The mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was extracted with ethyl acetate (100 mL×4). The organic layer dried over anhydrous sodium sulfate, purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1) to give ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, yield 30%). LC-MS (ESI) m/z: 404 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([F:8])=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1c(F)ccc(Cl)c1F
Yield: 92.2 %

Procedure:
A solution of 1,1-dimethylethyl (3-chloro-2,6-difluorophenyl)carbamate (437 mg, 1.66 mmol) in methanol (2 mL) was treated with 4 N hydrochloric acid in dioxane (2 mL) and heated for 1 min with a heat gun. After cooling, the volatile materials were removed in vacuo. The resulting residue was taken up in ethyl acetate and washed with sodium bicarbonate (sat). The organic phase was dried over magnesium sulfate, filtered, and concentrated yielding 3-chloro-2,6-difluoroaniline as a white solid (250 mg, 1.53 mmol, 92%). MS (EI) for C6H4ClF2N: 164 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[OH:23].[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=O)[CH:28]=[N:29][C:30]=1[CH2:31][OH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:4][C@H:3]2[OH:23])[CH:28]=[N:29][C:30]=1[CH2:31][OH:32]
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Reactant: O=Cc1cnc(CO)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NCc4cnc(CO)c(Cl)c4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 33 as a free base: 200 mg, 0.628 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (108 mg, 0.628 mmol) in DCE (10 ml) and Methanol (0.5 ml) was stirred at room temperature overnight. Sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred under N2 at rt for 6 h. LCMS showed imine and desired compound. An excess of sodium triacetoxyborohydride (399 mg, 1.885 mmol) was added. The mixture was stirred overnight. Full conversion to the amine was observed by LCMS. It was quenched with saturated NaHCO3, extracted with DCM/MeOH 9/1, dried (MgSO4), filtered, and concentrated affording 242 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (179.8 mg, 0.360 mmol, 57% yield) as a white solid.
Reaction SMILES: [C:1](N1C[C@@H](S)[C@H](N(C)S(C2C=CC(OC3C=CC=CC=3)=CC=2)(=O)=O)C1)(=O)N.[C:28]([N:35]1[CH2:39][C@@H:38]([S:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(O[K])(C)(C)C.CI>CN(C=O)C.C(OCC)(=O)C>[C:28]([N:35]1[CH2:39][C@@H:38]([S:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([N:45]([CH3:1])[S:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:53][CH:54]=2)(=[O:47])=[O:48])[CH2:36]1)([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29]
Reactant: CN([C@@H]1CN(C(N)=O)C[C@H]1S)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1SC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
(±)-N-Carbamoyl-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-mercaptopyrrolidine. To a solution of (±)-N-Boc-trans-3-(4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (236 mg, 0.466 mmol) in DMF (2 mL) at 0° C. was added tBuOK (0.69 mmol). The mixture was stirred at 0° C. for 10 min, then MeI (0.69 mmol) was added. The solution was stirred at 0° C. until TLC analysis showed no starting material remained. Ethyl acetate (20 mL) was added and the solution was extracted with water, then was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (ethyl acetate) to give (±)-N-Boc-trans-3-(N-methyl-4-phenoxybenzenesulfonamido)-4-tertbutylmercaptopyrrolidine as a white powder (240 mg, 99%): 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J=8, 2H), 7.44 (t, J=8, 2H), 7.24 (t, J=8, 1H), 7.10 (m, 2H), 7.09 (d, J=9, 2H), 4.22 (m, 1H), 3.90 (m, 1H), 3.37 (m, 2H), 3.08 (m, 2H) 2.86 (s, 3H), 1.44 (s, 9H), 1.28 (s, 9H); MS (ESI) m/e 520.2 (M+); HRMS (ESI) calculated for C26H36N2O5S2Na+ 543.1950. found 543.1950.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 16 h

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (50 mg 0.13 mmol) in dioxane (3 mL) at room temperature (20° C.) was added sodium hydrogencarbonate (22 mg 0.26 mmol) followed by ethyl chloroformate (14 uL 0.15 mmol). The reaction mixture was stirred for 16 h. The solvent was removed in vacuo and the residue partitioned between DCM and water. The organic phase was passed through a 1 micron PTFE filter to dry and then evaporated in vacuo to afford (38 mg 64%).