Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([CH:13]=[O:14])[C:11]=1[OH:18].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:18][C:11]1[C:10]([O:9][CH3:8])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])(=[O:3])[CH3:2]
Reactant: COc1cccc(C=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc(C=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Acetic anhydride (45.9 g, 0.45 mol) was added to a suspension of 3-methoxysalicylaldehyde (45.6 g, 0.3 mol) and K2CO3 (42.0 g, 0.6 mol) in CH2Cl2 (450 L) at rt. The reaction mixture was stirred at rt overnight then filtered, evaporated and the residue was recrystallised from cyclohexane to give 42 (42.0 g, 74%) as colourless needles:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH2:57]([N:54]1[CH2:55][CH2:56][N:51]([S:48]([C:44]2[CH:43]=[C:42]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:47]=[N:46][CH:45]=2)(=[O:50])=[O:49])[CH2:52][CH2:53]1)[CH3:58]
Reactant: CCN1CCN(S(=O)(=O)c2cncc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(S(=O)(=O)c2cncc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 1-(5-bromo-pyridine-3-sulfonyl)-4-ethyl-piperazine (prepared from 5-bromo-pyridine-3-sulfonyl chloride and N-ethylpiperazine, 70 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of (5-{7-[5-(4-ethyl-piperazine-1-sulfonyl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-bis-(4-methoxy-benzyl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-250) as a milky white powder (46 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2].[H-].[Na+].[Na+].[I-].Cl[CH2:26][C:27]1[S:31][C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH3:42]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH2:26][C:27]2[S:31][C:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[N:29][C:28]=2[CH3:42])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCOC(=O)COc1ccc(NC)cc1CCCOC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Reaction time: 0.5 h

Procedure:
To 0.216 g (0.77 mmol) of the above prepared [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester, dissolved in 2.4 ml of abs. DMF, were added successively at 0° C. 0.037 g of NaH (60% in mineral oil, 1.2 eq.), 0.115 g (1 eq.) of NaI and 0.215 g (0.96 eq.) of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (WO02/28433). The reaction was allowed to proceed for 5 min at 0° C. and for 0.5 h at ambient temperature. Pouring onto crashed ice/aqueous 10% KHSO4, twofold extraction with EtOAc, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=78/22), yielded 0.284 g of the title compound as light yellow oil, MS: 537.5 (MH)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18]CC3C=CC=CC=3)=[CH:13][C:12]=2[CH3:26])=[CH:9][C:8]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:12]([CH3:26])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=2[CH3:17])=[CH:9][C:8]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(-c2c(C)cc(OCc3ccccc3)cc2C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(C)=O)c(-c2c(C)cc(O)cc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of ethyl 6-(acetylamino)-4′-(benzyloxy)-2′,6′-dimethylbiphenyl-3-carboxylate (809 mg, 1.94 mmol), 10% palladium-carbon (50% water-containing product, 404 mg) and ethanol (10 mL) was stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (544 mg, yield 86%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCN
Product: CCNc1ccc([N+](=O)[O-])cc1N
Yield: 72 %

Procedure:
2-fluoro-5-nitroaniline (5 g, 32 mmol) and a solution of ethyl amine (32 ml, 2M in THF) were coupled according to the procedure of intermediate example one part A to give the title compound as a dark red solid 4.16 g, 72%). 1H NMR (300 MHz, d6-DMSO) δ7.51 (dd, J=8.7 and 2.7 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.86 (t, J=4.6 Hz, 1H), 5.15 (s, 2H), 3.20 (m, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH:13]=1)[CH:8]([CH3:10])[CH3:9])(C)(C)C.Br.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=1>>[Cl:36][C:31]1[CH:30]=[C:29]([CH2:28][NH:27][C:20]2[N:19]=[C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:7][CH:8]([CH3:9])[CH3:10])[CH:13]=3)[CH:23]=[CH:22][N:21]=2)[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: CC(C)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Reactant: NCc1ccc(O)c(Cl)c1
Agent: Br
Product: CC(C)NCc1cccc(-c2ccnc(NCc3ccc(O)c(Cl)c3)n2)c1

Procedure:
[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-isopropyl-carbamic acid tert-butyl ester (intermediate 70) was coupled with 4-Aminomethyl-2-chloro-phenol hydrobromide salt (Intermediate 121) following procedure F then deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 383. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.5 (s, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.8 (d, 1H) 7.7 (m, 1H) 7.6 (d, 1H) 7.4 (s, 1H) 7.2 (d, 1H) 6.9 (d, 1H) 4.3 (s, 1H) 3.6 (m, 2H) 3.5 (m, 1H) 1.4 (d, 6H)
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:48])=[CH:43][CH:42]=2)[CH:13]=[C:14]([Cl:40])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23]2)[C:18]1=[O:39]>C1COCC1>[Cl:40][C:14]1[CH:13]=[C:12]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:48])=[CH:45][CH:46]=2)[CH:11]=[C:10]([Cl:9])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)[C:18]1=[O:39]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCOCC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Add water (3 mL) and TFA (1 mL) to a solution of (R)-3-[3,5-Dichloro-4′-(morpholine-4-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one in THF (3 mL). Stir the mixture at room temp for 12 hours. Partition the reaction with ethyl acetate (20 mL) and sodium bicarbonate (sat. solution, 15 mL), separate the organic layer, extract the aqueous with another 20 mL of ethyl acetate, and combine the organic solutions. Dry over sodium sulfate, filter and concentrate. Dissolve the residue in 4 mL of dichloromethane, load on silica gel column, and flash with ethyl acetate for 15 minutes and then switch to 8% methanol in dichloromethane to afford 0.13 grams (84%) of the desired product as white solid. MS (m/z): 532 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:19]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2scc(C)c2c1
Product: Cc1ccc2sc(C(O)c3ccccc3)c(C)c2c1

Procedure:
Using general procedure B, 3,5-dimethyl-benzo[b]thiophene was reacted with benzaldehyde to give (3,5-dimethyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a colorless oil. MS: 251.4 ([M+H—H2O]+).
Reaction SMILES: C[SiH](C)[O:3][CH:4]1[C:8](C)(C)[CH2:7][O:6][C:5]1=[O:11].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15].[SiH3]O[SiH3]>>[OH:3][C@H:4]([CH2:8][CH2:7][OH:6])[C:5](=[O:11])[CH2:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C[SiH](C)OC1C(=O)OCC1(C)C
Agent: [SiH3]O[SiH3]
Product: O=C(CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)[C@H](O)CCO

Procedure:
Reaction of (R)-dihydro-3-tertbuty]dimethylsilyloxy-4,4-dimethyl-2(3H)-furanone with 4-(4′-trifluoromethoxyphenyloxy)-phenyl methyl sulfone as in Example 126A followed by silyl ether deprotection as in Example 125B gave the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][C@@H:36]([NH2:38])[CH3:37].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:38][C@@H:36]([CH3:37])[CH2:35][O:34][CH3:33])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC[C@H](C)N
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred suspension of carbaldehyde 321 (336 mg, 0.749 mmol), (S)-1-methoxy-2-aminopropane (200 mg, 2.248 mmol) and acetic acid (68 mg, 1.124 mmol) in DCM (20 ml) at rt under nitrogen was added NaBH(OAc)3 (418 mg, 1.873 mmol). The reaction mixture was stirred at rt overnight and quenched with a solution of 10% HCl. The layers were separated; the aqueous layer was collected, washed twice with DCM and basified with 4N NaOH (pH 12) to form a suspension that was stirred for 30 min. The solid was collected by filtration, rinsed with water and air-dried and purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 10/90) to afford the title compound 334 (182 mg, 0.35 mmol, 46% yield) as a yellow fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.91 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.17 (m, 1H), 6.64 (d, J=5.5 Hz, 1H), 6.57 (bd, J=2.7 Hz, 1H), 3.84 (d, J=14.5 Hz, 1H), 3.78 (d, J=14.5 Hz, 1H), 3.27 (dd, J=9.4, 6.3 Hz, 1H), 3.24 (s, 3H), 3.19 (dd, J=9.2, 5.5 Hz, 1H), 2.81-2.71 (m, 1H), 2.59-2.51 (m, 1H), 2.36-2.10 (m, 1H), 0.98 (d, J=6.3 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 522.4 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=434.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:27])[CH2:18][N:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20]>>[CH:21]1([N:19]([CH3:20])[CH2:18][CH:17]([OH:27])[CH2:16][NH:15][C:11]([C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=3[NH:3][C:2]=2[CH3:1])=[O:13])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CN(CC(O)CN)C1CCCCC1
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN(C)C1CCCCC1)CCCC2=O
Yield: 83 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(cyclohexyl(methyl)amino)propan-2-ol 0.39 g (2.1 mmol) were reacted to give 0.30 g (83%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[CH3:19][C:20]#[N:21].O>>[NH2:1][C:2]1[N:7]=[C:6]([N:21]2[CH2:12][CH2:11][CH2:10][CH2:15][CH2:19][CH2:20]2)[N:5]=[C:4]([NH:9][C@@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: Nc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Reactant: CC#N
Solvent: O
Product: Nc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of crude cis-4-(4-amino-6-chloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (˜0.46 mmol) in CH3CN/H2O (5 ml/1 ml) was added hexamethyleneimine (240 μl, ˜5 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction solution was condensed and the crude product was purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-65% CH3CN/H2O, 0.1% TFA, 18 min) to give the product (65 mg). MS (ES+): m/e 335.3 [M+H]+.
Reaction SMILES: [Na].[F:2][C:3]([F:14])([C:8]1[CH:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:4]([F:7])([F:6])[F:5].[CH3:15][N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](=[O:20])[CH2:18]Br>C(#N)C>[CH3:15][N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](=[O:20])[CH2:18][O:13][C:11]1[O:10][N:9]=[C:8]([C:3]([F:2])([F:14])[C:4]([F:7])([F:6])[F:5])[CH:12]=1
Reactant: CN(C(=O)CBr)c1ccccc1
Reactant: Oc1cc(C(F)(F)C(F)(F)F)no1
Agent: [Na]
Solvent: CC#N
Product: CN(C(=O)COc1cc(C(F)(F)C(F)(F)F)no1)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To 0.50 g (2.2 mmole) of 3-pentafluoroethyl-5-hydroxyisoxazole sodium salt were added dry acetonitrile (7 ml) and N-methyl-N-phenyl-2-bromoacetamide (0.55 g) and the resulting mixture was stirred at 60° C. for 24 hours. After completion of reaction, the reaction solution was evaporated under reduced pressure and to the residue was added water (80 ml), extracted with methylene chloride, treated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give 0.52 g of crystals. These crystals were recrystallized from n-hexane to give 0.48 g of the titled compound as colorless plates, yield 62.3%, m.p. 88.0-89.0° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)(C)(C)C.ClCCl.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O>[CH3:29][S:30]([O:15][CH2:14][C@H:12]1[O:11][C:10]([CH3:17])([CH3:16])[O:9][C@@H:8]([CH2:7][C:6]([OH:5])=[O:18])[CH2:13]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)O[C@H](COS(C)(=O)=O)C[C@H](CC(=O)O)O1
Reaction time: 1 h
Yield: 92 %

Procedure:
tert-Butyl-2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]acetate (10.0 g) and dichloromethane (60.0 mL) were added to a reactor. The reaction mixture was cooled to 0˜5° C. Triethylamine (12.9 mL) and methanesulfonyl chloride (3.6 mL) was added to the reaction mixture, which was then stirred at 0˜5° C. for 1 hour. Water (500.0 mL) was added to the reaction mixture under stirring. The separated organic layer was concentrated under reduced pressure. Methanol (40.0 mL), water (20.0 mL), and sodium hydroxide (3.4 g) were added to the resulting residue. The reaction mixture was stirred at 40° C. for over 12 hours and then concentrated under reduced pressure. Water (30.0 mL) and ethyl acetate (60.0 mL) were added to the resulting residue and then the pH of the reaction mixture was adjusted to 2.0˜4.0 using 6N hydrochloric acid solution. The separated organic layer was concentrated under reduced pressure to obtain [(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid as a gel form (10.0 g, yield 92%).
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[F:10][C:11]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:36][CH2:35]4)=[CH:32][N:33]=3)[CH:30]=2)[CH:22]=[CH:21][C:12]=1[C:13]([NH:15][CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14].CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][N:4]([CH3:5])[C:17](=[O:19])[CH:16]([NH:15][C:13](=[O:14])[C:12]1[CH:21]=[CH:22][C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:35][CH2:36]4)=[CH:32][N:33]=3)[CH:30]=2)=[CH:24][C:11]=1[F:10])[CH3:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (31 μL, 0.18 mmol) was added to a mixture of 2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoic acid (29.7 mg, 0.06 mmol), dimethylamine (4.0 mg, 0.09 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred overnight at RT and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=523.1.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:12])=[C:6]([Cl:35])[CH:5]=1.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:35][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:14]1[N:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(NC(=O)N(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-[3-cyclohexyl-3-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 1 h at ambient temperature to give the title compound as yellow solid. MS: m/e=493.3 [M+H+].
Reaction SMILES: C(S(C1C=CC(CNC(C2C=C3CN[C@@H](C(C)C)C3=NC=2)=O)=CC=1)(=O)=O)C.[CH2:28]([S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([NH:42][C:43]2[CH:44]=[C:45]3[CH2:51][N:50](C(OC(C)(C)C)=O)[C@@H:49]([CH:59]([CH3:61])[CH3:60])[C:46]3=[N:47][CH:48]=2)=[O:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH3:29]>>[CH2:28]([S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([NH:42][C:43]2[CH:44]=[C:45]3[CH2:51][NH:50][C@@H:49]([CH:59]([CH3:60])[CH3:61])[C:46]3=[N:47][CH:48]=2)=[O:41])=[CH:37][CH:38]=1)(=[O:32])=[O:31])[CH3:29]
Reactant: CCS(=O)(=O)c1ccc(CC(=O)Nc2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Agent: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CC(=O)Nc2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material. LC-MS tR=0.50 min in 1 min chromatography, MS (ESI) m/z 388.3 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.02 (s, 1H), 8.48 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.84 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.78 (m, 2H), 3.98 (s, 1H), 3.81 (s, 1H), 3.70 (s, 1H), 3.20 (q, J=7.6 Hz, 2H), 2.65-2.57 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=O)[C@@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO>O1CCCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C@@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=1
Reactant: O=C(c1ccco1)N1CCC[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccco3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1

Procedure:
The compound of Example 9 (340 mg) was dissolved in tetrahydrofuran. To this solution was added borane-dimethyl sulfide complex (0.18 ml of 10M solution) and the resulting solution was heated at reflux for 8 h. The mixture was cooled, methanol added to quench excess borane, and the solvents were removed in vacuo. The residue was dissolved in methanol (10 ml) and potassium carbonate was added (238 mg). This mixture was heated at reflux for 1 hour; the methanol was removed in vacuo and the residue was dispersed between ethyl acetate and brine. The ethyl acetate layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on silica using 10% ethyl acetate in petrol. The product was recrystallised from ether-hexane: mp 103°-104° C. 1H NMR d 1.4-1.5 (2H, m, CH2CH2), 1.8-1.9 (1H, m, CHHCH2N), 2.1-2.2 (2H, m, CHHCH2N and CHHN), 2.95-3.0 (1H, m, CHHN), 3.11-3.15 (1H, d, J=15.0 Hz, NCHH-furan), 3.38 (1H, s, NCHCHO), 3.54-3.58 (1H, d, J=15.0 Hz, NCHH-furan), 3.56 (1H, s, NCHCHO), 4.02-4.06 (1H, d, J=13.0 Hz, OCHH--), 4.59-4.62 (1H, d, J=13.0 Hz, OCHH--), 6.08-6.09 (1H, m, furan H), 6.35-6.36 (1H, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H, m, ArH), 7.55 (1H, s, furan-H), 7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI+) m/z 485 (M+ +1, 100%). Found: C, 62.11; H, 4.80; N, 2.90. Calcd. for C25H23NF6O: C, 62.27; H, 4.83; N, 2.96.