Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@H:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 42 h

Procedure:
6.0 g (33.3 mmol) of ethyl 4-hydroxyphenylacetate, 6.25 g (33.3 mmol) of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine and 10.5 g (40 mmol) of triphenylphosphine were dissolved in 125 ml of tetrahydrofuran. 6.3 ml (40 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 42 hours. After the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][C:5]2[CH:13]=[CH:14][S:15][C:4]=2[S:3]1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]2[CH:13]=[CH:14][S:15][C:4]=2[S:3]1
Reactant: CCOC(=O)C1=Cc2ccsc2SN1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CN1Sc2sccc2C=C1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
To a solution of the product from Step B (1.00 g, 3.66 mmol) in anhydrous THF (20 mL) at -70° C. was added DIBAL (1.0M, 7.69 mL, 7.69 mmol). The mixture was warmed to ambient temperature and stirred for 2 h, additional DIBAL (20 mmol) was added and the reaction was stirred for 18 h. Methanol (100 mL) was added and the reaction mixture was evaporated to a residue which was suspended in 2N HCl (50 mL) and extracted with ethyl acetate (2×80 ml). The combined extracts were dried (MgSO4) and evaporated to give a solid which was recrystallized from ethyl acetate/hexane to give the desired product (0.80 g, 95%): mp 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 4-(3-bromophenyl)butyl ester (2.3 g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) in DMSO was heated up to 80° C., stirred for 1.5 hours and monitored by NMR. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of this residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent gave 5-(3-bromo-phenyl)pentanenitrile as a colorless oil (1.12 g, 78% yield). m/e (M)+ 237; 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.63-2.65 (m, 2H), 2.75-2.78 (m, 2H), 2.35-2.38 (m, 2H), 2.60-2.63 (m, 2H), 7.05-7.10 (m, 2H), 7.25-7.28 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chlorobenzoic acid (200 mg, 0.849 mmol) was refluxed in the presence of concentrated sulfuric acid (5.49 mg, 0.042 mmol) in methanol (10 mL) at 70° C. for overnight. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (130 mg). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, 1H, J=2.0 Hz), 7.91 (dd, 1H, J=2.0 & 8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 3.92 (s, 3H). ESI-MS: 250.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24]C4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2OCC[C:48]3[C:44](=[N:45][N:46]([C:52]4[N:53]([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=5[Cl:63])[N:54]=[CH:55][N:56]=4)[CH:47]=3)C=2C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:48]4[C:44](=[N:45][N:46]([C:52]5[N:53]([C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=6[Cl:63])[N:54]=[CH:55][N:56]=5)[CH:47]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccccc4Cl)cc2CCO3)CC1
Yield: 80 %

Procedure:
4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared similarly to 4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from 9-bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (500 mg, 1.13 mmol) to give 4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colourless gum (490 mg, 80%). LCMS RT=5.14 min, M+Na+=567
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl>CS(C)=O>[Cl:16][C:17]1[C:18]([O:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1CCCCC1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1CCCCC1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of (2-methylcyclohexyl)methanol (1.28 g, 9.99 mmol) in anhydrous dimethylsulfoxide (20 mL) was added cesium carbonate (5.87 g, 18.06 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (2.23 g, 8.96 mmol). The reaction mixture was stirred at 70° C. for 16 hours; cooled to ambient temperature and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (2×15 mL), the combined organics were washed with brine (15 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (2.30 g, 72%); MS (ES+) m/z 303.2, 301.2 (M−54); MS (ES−) m/z 301.2, 299.2 (M−56).
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)/[C:7](=[O:16])[NH:8]2
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1c([N+](=O)[O-])ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1N)/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
(Z)-4-Azido-1,3-dihydro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (340 mg, 1.15 mmol)(from Example 11) was dissolved in THF at rt (30 mL). Ammonium hydroxide was added (0.36 ml), followed by a catalytic amount of poisoned platinum on carbon (5% Pt/C•½S, 50 mg) (Engelhard Industries). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 2.5 h. The mixture was filtered through a cake of Celite®, and the cake was washed twice with THF. The hydrogenation was repeated with a fresh batch of catalyst, solvent and ammonium hydroxide (50 psi, 2 h). After filtration through Celite®, the mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 75% ethyl acetate in hexanes) to yield (Z)-4,5-diamino-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 160 mg, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39](=O)[CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:39][CH3:40])[C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC=O
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of tert-butyl 3-(3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (0.90 g, 1.69 mmol) and acetaldehyde (0.22 g, 5.06 mmol) in dichloroethane (10 mL), was added acetic acid (0.61 g, 10 mmol) and the reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (1.07 g, 5.05 mmol) was added at 0° C. and the reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure giving the title compound which was used without further purification (0.85 g).
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7](=[CH:10]OC)[C:8]#[N:9])([CH3:3])[CH3:2].[S:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([NH2:30])=[NH:29])[CH2:23][CH2:22]1>>[CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7]1[C:8]([NH2:9])=[N:29][C:28]([NH:27][CH:24]2[CH2:25][CH2:26][S:21][CH2:22][CH2:23]2)=[N:30][CH:10]=1)([CH3:2])[CH3:3]
Reactant: COC=C(C#N)Oc1cc(OC)c(OC)cc1C(C)C
Reactant: N=C(N)NC1CCSCC1
Product: COc1cc(Oc2cnc(NC3CCSCC3)nc2N)c(C(C)C)cc1OC

Procedure:
5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N*2*-(tetrahydro-thiopyran-4-yl)-pyrimidine-2,4-diamine was prepared according to the procedure of example 5, using 2-(2-isopropyl-4,5-dimethoxy-phenoxy)-3-methoxy-acrylonitrile (prepared using the procedure of Example 4) together with N-(tetrahydro-thiopyran-4-yl)-guanidine from Preparation 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1
Reactant: CC(C)COC(=O)N1CCN(c2nccc(Cl)n2)CC1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)N1CCN(c2nccc(-c3ccccc3C(F)F)n2)CC1
Temperature: 120 °C

Procedure:
To a solution of the isobutyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate 8a and 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 11a (1.2 eq) in acetonitrile was added Pd(PPh3)4 (0.10 eq), K2CO3 (2 eq) and water. The vial was sealed and heated by microwave irradiation at 120° C. for 15 minutes. The solvent was evaporated and the residue was dissolved in DMF and purified by reverse phase HPLC (using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 24. m/z 391.1 (M+1), r.t: 3.59 (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 5-methoxy-2-methylaniline (20 mg, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (18 mg, 52%). 1H NMR (CDCl3): 8.85–8.82 (m, 1H), 8.59–8.56 (m, 1H), 7.90–7.84 (m, 1H), 7.45–7.40 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J=2.6, 8.3 Hz, 1H), 6.69 (s, 1H), 3.81 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]([C:34]([NH:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([N:5]([C:34]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:35])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)NCC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCN(C(=O)NCC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl {[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)carbonyl]amino}acetate (which was obtained in Example 379) by NaOH hydrolysis as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.1 Hz, 3H), 1.15-1.60 (m, 6H), 1.85-2.00 (m, 2H), 2.65-2.95 (m, 5H), 2.92 (s, 3H), 3.42 (d, J=4.0 Hz, 2H), 3.45-3.55 (m, 2H), 3.65-3.80 (m, 2H), 4.65-4.75 (m, 1H), 5.16 (t, J=4.0 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.95-7.15 (m, 5H), 7.20 (d, J=2.0 Hz, 1H); MS (ES) m/z: 576.3 (M−H)−; HRMS Calcd. for C27H38N5O7S(M−H)−: 576.2497. Found: 576.2502.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(F)cc1F
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
A solution of 2,4-difluorobenzoic acid (1.5808 g, 10.00 mmol) in methanol (15 ml) was cooled to 0° C. in ice-water bath. To the mixture was added dropwise a solution of thionyl chloride (1.46 ml, 20.02 mmol) in methanol (10 ml). The mixture was gradually warmed to room temperature and stirred for 24 hours. The mixture was added to sat. NaHCO3 aqueous solution, extracted three times with ether and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (1.6743 g; 97%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([C:33](O)=[O:34])=[CH:31][N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:26]3[C:27]([S:28][CH:29]=[C:25]3[CH3:24])=[N:30][CH:31]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1csc2ncc(C(=O)O)n12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3scc(C)n23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=492.0.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:37]([C:36]1[CH:39]=[CH:40][C:33]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:34][CH:35]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
0.61 ml (3.07 mmol) of diisopropyl diazene-1,2-dicarboxylate is added drop by dr op at 0° C. under argon to 0.5 g (2.05 mmol) of tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate, 0.3 g (2.46 mmol) of 4-hydroxybenzaldehyde and 1 g (3.07 mmol) of supported triphenylphosphine (3 mmol/g of resin) diluted in 14.5 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at room temperature for 20 hours, and then the solid is filtered and rinsed with dichloromethane. The filtrate is concentrated and diluted in sodium hydroxide solution (1 M), the product is extracted several times with ethyl acetate, and then the organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 4:6 cyclohexane/ethyl acetate to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-1-carboxylate in the form of a colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[CH:21]=1)=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3.[CH:25](N1CCCCC1)=[O:26].Cl>C(OCC)C.O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[C:21]=1[CH:25]=[O:26])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2C
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 179.9 %

Procedure:
16.25 ml of n-butyllithium solution (1.6M in hexane) were added dropwise at -78° under argon to a solution of 5.46 g (10.0 mmol) of 3,7-dimethoxy-10-methylphenothiazine in 100 ml of diethyl ether/tetrahydrofuran (4:1). The reaction mixture was stirred at -70° for 15 minutes, brought slowly to 0°, stirred for 2 hours and then treated at 0° with 3.39 g (30.0 mmol) of N-formylpiperidine. After stirring at 0° for 2 hours the mixture was poured into 500 ml of ice-water, whereupon it was acidified slightly with 0.5N hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases, were extracted with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was crystallized from acetone, whereupon, after drying, 5.42 g (90%) of 3,7-dimethoxy-10-methyl-phenothiazine-4-carbaldehyde were obtained as a red solid of m.p. 150°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].Cl[C:16]1[N:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]2[N:21]=[C:20]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH:19]=[CH:18][N:17]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: Cc1cc(N)cc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cccnc2)c1
Temperature: 75 °C

Procedure:
3-Methyl-5-(pyridin-3-yl)aniline (50.7 mg, 0.275 mmol) was added a solution of tert-Butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (72.0 mg, 0.229 mmol) in dioxane (486 μL). The reaction mixture was flushed and purged with Ar(g) followed by the addition of Pd(OAc)2 (5.15 mg, 0.023 mmol) and Xantphos (19.9 mg, 0.034 mmol). The reaction was heated to 75° C. overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes, 10:90 to 50:50) to yield tert-butyl 4-[(2-{[3-methyl-5-(pyridin-3-yl)phenyl]amino}pyrimidin-4-yl)oxy]piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[NH:19][C:20](=O)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:19]=[C:20]([CH3:21])[NH:16][C:11]=2[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.4 %

Procedure:
A mixture of N-[2-(benzyloxy)-4-bromo-6-nitrophenyl]acetamide (120 g, 329 mmol, Step 1 of Example 1) and iron powder (55.1 g, 986 mmol) in acetic acid (500 mL) was refluxed with stirring for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (1.5 L). The resulted precipitates were filtered through a pad of Celite, and washed with ethyl acetate (500 mL). The filterate was concentrated in vacuo, and the residue was diluted with ethyl acetate (200 mL). The brine (800 mL) was added to the organic mixture, the resulted white precipitates were collected by filtration, and washed with water (200 mL) and diethyl ether (200 mL). The white solid was dissolved with dichloromethane/methanol (10:1, 1.0 L), dried over magnesium sulfate, and concentrated. The solid was triturated with diethyl ether (300 mL), collected by filtration, and dried in vacuo to afford the title compound as a white solid (54.7 g, 53%).