Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[C:6]=2[CH:15]=1.[CH:16]([N:19]1[CH:23]=[N:22][N:21]=[C:20]1S(C)(=O)=O)([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][N:9]([C:20]4[N:19]([CH:16]([CH3:18])[CH3:17])[CH:23]=[N:22][N:21]=4)[CH:10]=3)[C:6]=2[CH:15]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: CC(C)n1cnnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)n1cnnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 150 °C
Yield: 43.2 %

Procedure:
To a microwave vial were charged 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (200 mg, 0.755 mmol), 4-isopropyl-3-methanesulfonyl-4H-[1,2,4]triazole (143 mg, 0.755 mmol), cesium carbonate (246 mg, 0.755 mmol) and THF (2 mL). The reaction mixture was heated to 150° C. for 2 h then extracted with ethyl acetate (20 mL), washed with water (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane) to afford 9-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (122 mg, 43%). LCMS RT=4.34 min, M+H+=374/376.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:36])[C@@H:24]([NH:28]C(OCCCC)=O)[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>C(OCC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:36])[C@@H:24]([NH2:28])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2ccc(Cl)cc2)c(OC)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.8 g of (S)-2-(butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide and 5 g of concentrated hydrochloric acid are stirred for 10 minutes in a mixture of 20 ml of diethyl ether and 20 ml of dichloromethane at 0° C. Stirring is continued overnight at room temperature. The reaction mixture is introduced into 100 ml of 2N hydrochloric acid and extraction is carried out twice using 150 ml of diethyl ether each time. The aqueous phase is adjusted to pH 11 with 5M sodium hydroxide. Extraction is then carried out twice using 150 ml of ethyl acetate each time. The organic phases are washed twice with 50 ml of saturated sodium chloride solution each time, dried over sodium sulfate and concentrated, yielding (S)-2-amino-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 115-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c[nH]c3ccccc23)cc1
Agent: FB(F)F
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Clc1ccc(C2CNc3ccccc32)cc1

Procedure:
Using the same procedure as detailed in Example 1 3.5 g of 3-p-chlorophenylindole, 35 ml of glacial acetic acid, 7 ml of boron trifluoride etherate and 7 g of zinc dust were reacted together and the product worked up as in Example 1. In this way 1.5 g of the desired 3-p-chlorophenylindoline was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[CH2:8][CH2:9][O:10][CH3:11].[H-].[Na+]>CN(C=O)C.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:11][O:10][CH2:9][CH2:8][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COCCn1ccnc1C
Temperature: 80 °C
Yield: 66.1 %

Procedure:
To a solution of 2-methyl-1H-imidazole (1.0 g, 12.2 mmol) and 1-chloro-2-methoxyethane (1.34 ml, 14.62 mmol) in DMF (15 ml) was added sodium hydride (0.49 g, 12.2 mmol). The reaction mixture was heated to 80° C. for 18 hrs. The reaction mixture was transferred to a microwave vial and heated to 80° C. under microwave conditions for 1 hr. The reaction mixture was diluted with DCM (40 ml) and aq. 2M Na2CO3 (30 ml) and water (40 ml). The aqueous layer was re-extracted with DCM several times. The residue was purified by reverse phase chromatography (C18, 100% water) to afford the title compound (1.13 g, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[O:11][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(NC(N)=O)cc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(Nc2ccc(C)c(O)c2)n1
Temperature: 60 °C
Yield: 50 %

Procedure:
A solution containing 1-(3-hydroxy-4-methylphenyl)urea (150 mg, 0.9 mmol) and ethyl 3-bromopyruvate (0.11 mL, 0.9 mmol) in dry DMF (3.611E) was heated at 60° C. for 6 h. The reaction mixture was diluted with EtOAc and washed with brine and saturated NaHCO3 solution and the combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (hexane:EtOAc 6/4) to give the product in 50% yield (119 mg).
Reaction SMILES: [SH:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].[OH-].[Na+]>O1CCCC1.O>[CH2:21]([S:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4])[CH3:22]
Reactant: CCI
Reactant: O=C(CS)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
15 g of 4-mercaptoacetylaminobenzoic acid are dissolved in 450 ml of tetrahydrofuran, and 39.2 g of potash and 17.24 ml of ethyl iodide in 50 ml of tetrahydrofuran are added thereto. The mixture is stirred overnight and 200 ml of water and a small amount of 2N NaOH are added thereto. The cloudy solution is filtered, and the filtrate is acidified with concentrated HCl. The yellow crystals are filtered off with suction and recrystallised from isopropanol, yielding 4-ethylmercaptoacetylaminobenzoic acid having a melting point of 209°-211°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:37])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([I:11])[C:3]=12.[ClH:38]>O1CCOCC1>[ClH:38].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:37])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([I:11])[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)OC(C)(C)C)CC1)n1nc(I)c2c(N)ncnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate D14, 1.5 g, 2.441 mmol) was suspended in 1,4-Dioxane (5 ml) and 4 M HCl in dioxane (15.26 ml, 61.0 mmol) was added. The mixture was stirred at rt for 4 h, then volatiles were removed under reduced pressure to give title compound (1.56 g) as a light pink powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1.[CH3:34][S-:35].[Na+].C(O)(=O)C>CN(C=O)C>[O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:35][CH3:34])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 11; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Sodium methanethiolate (200 mg, 2.85 mmol) was added and the mixture was stirred for 2 hours at 50° C. Acetic acid (0.4 ml) was added and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 450 mg (96%). NMR (300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9–7.1 (m, 3H), 7.2–7.4 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[C:9]1[C:27]([NH2:28])=[N:26][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:28][C:27]1[C:9]([C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Br:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[N:13][C:12]=2[N:26]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Br)cccc3Br)c(NC(=O)NC(C)(C)C)nc2n1
Yield: 52.9 %

Procedure:
6-(2,6-Dibromo-phenyl)-N2 -[3-diethylamino-propyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (0.34 g) from Example 61 was reacted with 0.066 g of tert-butyl isocyanate according to the general procedure of Example 54. The crude residue was purified by thin layer chromatography with ethyl acetate:ethanol:triethylamine (9:2:1) followed by preparative HPLC chromatography using a Vydac 218 TP 1022 reverse phase column with a gradient elution of 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid/acetonitrile to give 0.214 g of the title compound, ESMS (20/80 MEOH/CH3CN+0.1% AcOH): 606=M+ +H; mp dec. >45° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:24]=[N:23][CH:22]=[C:21]3[C:16]=2[CH2:17][CH2:18][N:19]([C:25](OC(C)(C)C)=O)[CH2:20]3)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[C:16]3[CH2:17][CH2:18][N:19]([CH3:25])[CH2:20][C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate was dissolved in MeOH (8 mL). Acetic acid (91.88 mg, 87.01 μL, 1.530 mmol), formaldehyde (37% solution in water, 99.33 mg, 91.13 μL, 1.224 mmol) and NaBH(OAc)3 (324.3 mg, 1.530 mmol) was sequentially added and the mixture was stirred for 1 hour at RT. The reaction mixture was partitioned between an aqueous saturated solution of NaHCO3 and DCM. The insoluble was filtered off and the combined organic extract was dried and concentrated in vacuo. The insoluble and the residue were combined and purified by fractionlynx to yield 2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 342.2.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14]>S(=O)(=O)(O)O.O>[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[OH:14]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 29045.2 %

Procedure:
Sodium nitrate (28 g, 0.33 mmol) was dissolved in the solvent mixture of 70 mL of concentrated sulfuric acid and 210 mL of water at −5° C., followed by slowly dropwise addition of 2-bromo-4-methyl-phenol 11a (30.8 g, 0.165 mol). The reaction mixture was reacted for 2 hours upon cooling by an ice-water bath. The mixture was warmed up to room temperature and reacted for another 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with 200 mL of ethyl acetate. The combined organic extracts were washed with water (100 mL×5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-4-methyl-6-nitro-phenol 11b (22.24 g, yield 58.1%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:4][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:23])(=[O:24])=[O:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-])C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 291C (4.14 g) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 2 hours. The mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (300 mL) and washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: BrBr.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](C2C=CC(C(C)(C)C)=CC=2)[CH3:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH2:14])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1
Agent: BrBr
Product: C=Cc1ccc(C(C)(C)C)cc1

Procedure:
The bromine number of the recovered 1,1-bis(p-t-butylphenyl)ethane was 3.81. According to mass spectrometry, the content of the component of m/e=292 was 7.5%.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in methylene chloride (5 mL) was treated with triethylamine (0.3 mmol), DMAP (0.01 mmol) and pivalyl chloride (0.15 mmol). The reaction was stirred for 3 h at room temperature and concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with water (2×5 mL). The organic layer was concentrated and the residue purified by Gilson reverse phase HPLC to provide the title product as a white powder (82%). ESMS [M+H]+: 563.2
Reaction SMILES: O.Cl.[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47](Cl)(=[O:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Zn].C(Cl)(Cl)Cl>[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47]([OH:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)O)c1
Reaction time: 0.5 h

Procedure:
87 ml of water and 18.2 ml (0.218 mol) of 12N-HCl were added to the solution of 87 ml of chloroform and 8.65 g (0.0121 mol) of the white solid containing 3,5-dihexadecyloxycarbonylbenzenesulfonyl chloride, and then 7.93 g of zinc was added thereto at 5° C. followed by stirring for 4 hours and 30 minutes. After the insoluble component was removed therefrom, the solution was extracted with 100 ml of chloroform, washed with saturated brine, and dried with Glauber's salt. After removing Glauber's salt, the solution was concentrated under reduced pressure, and the residue was recrystallized from hot hexane to obtain a colorless crystal of 3,5-dihexadecyloxycarbonylbenzenesulfinic acid. (Yield: 4.43 g, 48% (based on sodium 3,5-dimethyloxycarbonylbenzenesulfonate), m.p.: 63°-65° C.)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].CI>C1COCC1.O.C(OCC)(=O)C>[CH3:1][N:9]1[C:10]([Br:16])=[C:11]([Br:15])[C:12]([C:13]#[N:14])=[C:8]1[Br:7]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(Br)c(Br)c(C#N)c1Br
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 0.87 g (7.75 mmol) of potassium t-butoxide in 30 mL of dry THF under a nitrogen atmosphere is added dropwise from an addition funnel 2.10 g (6.39 mmol) of 2,4,5-tribromopyrrole-3-carbonitrile in 20 mL of dry THF. After 15 minutes, 0.64 mL (10.3 mmol) of methyl iodide is added by syringe over 2 minutes. After several hours at room temperature, the mixture is diluted with 100 mL of water and 75 mL of ethyl acetate. The separated water
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.[Mg+2]>>[N:27]1([C:14](=[O:15])[CH:13]([NH:12][C:10]([C:7]2[CH:6]=[C:5]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:8]=2)=[O:11])[C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: C1CNC1
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mg+2]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)N1CCC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and azetidine (CAN 503-29-7) as starting materials and isolated (29 mg, 54%); MS (ESI, m/z): 414.6 (M+H+).
Reaction SMILES: C1C=C([O:7]O)C(C(O)=O)=C(C(O)=O)C=1.[C:15]([O:23][CH2:24][CH:25]1[S:29][CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:15]([O:23][CH2:24][CH:25]1[S:29](=[O:7])[CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCC1OCCS1)c1ccccc1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCC1OCCS1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Monoperoxyphthalic acid, magnesium salt (MMPP, 28 g) was added portionwise under vigorous stirring to a mixture of 2-benzoyloxymethyl-1,3-oxathiolane (example 2) (20 g), tetrabutyl ammonium bromide (0.4 g) in methylene chloride (200 ml), and water (200 ml). The mixture was stirred at room temperature for 30 minutes and the organic layer was collected. The aqueous phase was extracted with methylene chloride (3×75 ml) and the combined organic layer was washed first with water (2×100 ml), then with brine solution (100 ml), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate as eluant to give 18.5 g (86%) of pure product as a mixture of cis- and trans- isomers in a ratio of 1:2 respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].N1C=CC=CC=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20]>CC(N(C)C)=O>[CH2:19]([O:21][C:22]([N:9]([C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:12])[NH2:10])=[O:23])[CH3:20]
Reactant: NNC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N(N)C(=O)c1cc(Cl)ccc1O
Temperature: 90 °C

Procedure:
37.2 g of 5-chloro-2-hydroxybenzoic acid hydrazide are dissolved in 200 ml of dimethylacetamide and 16 g of pyridine and 22 g of chloroformic acid ethyl ester are added simultaneously over the course of 30 minutes. The reaction mixture is subsequently heated to 90° C for 3 hours whilst stirring, cooled and poured onto 1 litre of ice water. The precipitate which has separated out slowly crystallises throughout. The N-(5-chloro-2-hydroxybenzoyl)-hydrazinecarboxylic acid ethyl ester thus obtained (Stabiliser No. 11) is isolated, washed with water and recrystallised from ethanol. Melting point 172° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][CH2:18][C:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Bromine (80 mmol) was added dropwise over 5 min to a stirred solution of 4′-benzyloxyacetophenone (70 mmol) in 40 ml chloroform. This mixture was stirred for an additional 5 min and quenched with saturated sodium bicarbonate in water until the pH reached 7. The organic layers were combined, dried over MgSO4, and concentrated to dryness. The crude mixture was purified over a silica gel column and eluted with methylene chloride to yield 2-bromo-4′-benyloxyacetophenone. An Rf of 0.62 was observed when resolved by thin layer chromatography using methylene chloride. 1H nmr (δ, ppm, CDCl3), 7.97 (2H, δ, 9.2 Hz, O—Ar—C(O)), 7.43 (5H, m, Ar′CH2O—), 7.04 (2H, δ, 9.0 Hz, O—Ar—C(O)), 5.15 (2H, s, Ar′CH2O—), 4.40 (2H, s, CH2Br).