Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl>[C:22]([O:21][C:19](=[O:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(N)c(CO)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2-amino-5-methyl-phenyl)-methanol (18.08 mmol, 2.48 g) in 50 mL CH2Cl2 was added Et3N (20 mmol, 2.8 mL) was added BOC2O and the reaction was allowed to stir overnight at r.t. for two days. The reaction mixture was washed with dilute HCl solution. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. (2-Hydroxymethyl-4-methyl-phenyl)-carbamic acid tert-butyl ester was obtained as a golden yellow thick oil (4.2 g) which was used in the next step without purification. MS (electrospray): mass calculated for C13H19NO3, 237.14; m/z found 238, [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](O)[CH:39]=1.N(/C(OCC)=O)=N/C(OCC)=O>O1CCCC1>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:1][CH2:2][CH:3]2[O:8][C:7]3[C:9]4[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=3[S:5][CH2:4]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:39]=1
Reactant: Oc1cccnc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Agent: CCOC(=O)/N=N\C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC(COc1cccnc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.35 g, 1.34 mmol) in tetrahydrofuran (10.0 mL) was added triphenylphosphine (1.4 g, 5.34 mmol) and pyridin-3-ol (0.507 g, 5.34 mmol) followed by diethyl (Z)-diazene-1,2-dicarboxylate (0.53 mL, 3.34 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched by addition of water (30 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The organic extracts were combined and extracted thrice with 1.0N HCl (10 mL). The HCl extracts were combined and its pH adjusted to 9 with a saturated sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2×20 mL), extracts combined, dried with sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 50% EtOAc in hexanes to 80% EtOAc in hexanes) to give the product as a purple solid (0.065 g, 14%). M.p.=153-155° C.; 400 MHz 1H NMR (CDCl3) δ: 8.43-8.35 (m, 1H), 8.33-8.24 (m, 1H), 8.05-7.94 (m, 1H), 7.72-7.56 (m, 2H), 7.56-7.4 (m, 2H), 7.33-7.2 (m, 1H), 4.98-4.86 (m, 1H), 4.54-4.34 (m, 2H), 3.34-3.16 (m, 2H); LCMS: 340 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:10]([CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:13]([O-:15])=[O:14])=O.Cl.[C:25]1(C)C=CC=C[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6]/[CH:10]=[C:12](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)\[C:13]([O:15][CH2:25][CH3:26])=[O:14]
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1cccc(OC)c1)c1ccc(OC)cc1
Yield: 70 %

Procedure:
A solution of 3-methoxyaniline (1.75 ml, 15.57 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (3.81 g), 1.1 eq) in toluene (25 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (15 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 3.57 g (70%) of compound 25 (Z isomer) in the form of a white solid which crystallizes from methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][C:3]=1[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>O1CCCC1.[Pd]>[CH3:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][CH:2]=[C:3]([CH2:13][CH2:14][CH3:15])[N:4]=1
Reactant: CCCc1nc(C)c(C(=O)OC)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cnc(C(=O)OC)c(C)n1
Reaction time: 8 h

Procedure:
To a solution of methyl 6-chloro-3-methyl-5-propylpyrazine-2-carboxylate (3.00 g, 13.1 mmol) and triethylamine (1.83 mL, 13.1 mmol) in tetrahydrofuran (40 mL) was added palladium on carbon (5%, M, wet, 300 mg) at 0° C. under argon. The reaction mixture was stirred for 8 h under hydrogen atmosphere, and then filtrated through celite with tetrahydrofuran. To the filtrate was added manganes dioxide (1.0 g) at room temperature. After being stirred overnight, the reaction mixture was filtrated through celite with tetrahydrofuran. The filtrate was concentrated in vacuo, and the residue was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 13:7) to give methyl 3-methyl-5-propylpyrazine-2-carboxylate. MS (APCI): m/z 195 (M+H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]3([OH:21])[C:13]4[C:18]([C:19](=[O:20])[C:10]3([OH:22])[C:9]=2[CH:23]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:3][CH3:4])[CH3:2].[C:24]([OH:27])(=O)[CH3:25].N1C=CC=CC=1.C1C[O:37][CH2:36][CH2:35]1>>[C:36]([O:12][C:8]1[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:23][C:9]=1[C:10]1([O:22][C:24](=[O:27])[CH3:25])[C:11](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])(=[O:37])[CH3:35]
Reactant: CC(=O)O
Reactant: CCC(C)c1ccc2c(c1)C1(O)C(=O)c3ccccc3C1(O)O2
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C)c1ccc(OC(C)=O)c(C2(OC(C)=O)C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
8-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (0.58 g, 1.8 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.39 ml, 3.7 mmol), pyridine (0.15 ml, 1.8 mmol), and 4-dimethyl aminopyridine (0.06 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (0.70 g, 48%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=5)[CH:20]=4)[NH:15][N:14]=3)=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C[OH:35]>C(Cl)Cl.C1COCC1>[C:3]([OH:2])(=[O:35])[CH3:12].[C:3]([OH:2])(=[O:35])[CH3:12].[NH2:29][C:25]1[N:24]=[C:23]([NH:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]3)=[CH:7][CH:8]=2)[CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc2ccc(-c3n[nH]c4ccc(Nc5ccnc(N)n5)cc34)cc2c1
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)O
Product: Nc1nccc(Nc2ccc3[nH]nc(-c4ccc5ccc(O)cc5c4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 4-[3-(7-methoxy-naphthalen-2-yl)-1H-indazol-5-ylamino]-pyrimidine-2-amine (Preparation #28 followed by general procedure N and F, 20 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added 1M BBr3 in THF (1 mL). The mixture was stirred for about 2 hours at room temperature then methanol (1 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to give 7-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-3-yl]-naphthalen-2-ol diacetate (12 mg, 60%); (DMSO-d6, 400 MHz) δ9.08 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 7.80 (m, 2H), 7.72 (d, 1H), 7.53 (d, 1H), 7.16 (s, 1H), 7.11 (d, 1H), 6.06 (bs, 2H), 5.99 (d, 1H), 1.87 (s, 6H); RP-HPLC (Table 1, Method e) Rt 1.43 min; m/z: (M+H)+ 369.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])P(OC)(OC)=O.C1CCN2C(=NCCC2)CC1.[CH3:30][C:31]1([CH3:42])[O:35][C:34]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:33]=2[O:32]1>C(Cl)Cl.[Cl-].[NH4+]>[CH3:1][O:2][C:3](=[O:18])/[C:4](/[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:40]/[C:38]1[CH:37]=[CH:36][C:34]2[O:35][C:31]([CH3:42])([CH3:30])[O:32][C:33]=2[CH:39]=1
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of methyl2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (5255 mg, 17678 μmol) in 25 mL of DCM at 0° C. was added DBU (2665 μl, 17678 μmol) dropwise. To the mixture was then added a solution of 2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde (3000 mg, 16836 μmol) in 10 mL of DCM over 5 minutes so as to maintain internal temperature below 10° C. The reaction was warmed to rt and stirred overnight before being diluted with DCM (25 mL) and poured in saturated ammonium chloride (100 mL). The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with 10% aqueous sodium bicarbonate then water then brine and dried over Na2SO4. Concentration under reduced pressure and purification by silica gel provided (Z)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5005 mg, 85.1% yield) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li:15])CCC.C1([Se][Se]C2C=CC=CC=2)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH:1]1([N-:7][CH:8]([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+:15]
Reactant: [Li]CCCC
Reactant: CC(C)NC1CCCCC1
Agent: c1ccc([Se][Se]c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)[N-]C1CCCCC1
Product: [Li+]
Reaction time: 2 h

Procedure:
Lithium cyclohexylisopropylamide was prepared from cyclohexylisopropylamine (0.07 ml) and n-butyllithium (1.6-M, 0.265 ml) in THF (1 ml). To the resultant was added dropwise a solution of methyl ester (34) (0.1412 g) in THF (4 ml) and stirred for 2 hours. A solution of diphenyl diselenide (0.132 g) and HMPA (0.074 ml) in THF (2 ml) was added, and the mixture was stirred at -70° C. for one hour and -40° C.--30° C. for 1.5 hours. According to the conventional treatment, selenide (35) (0.1247 g) was obtained. Selenide (35) (0.1247 g) was dissolved in ethyl acetate (6 ml) and methanol (4 ml), and stirred at room temperature with aqueous hydrogen peroxide (30%) (0.5 ml) for one hour. The crude product obtained by the conventional treatment was chromatographed (ethyl acetate/hexane (1:6)) to give Δ2 -PGE2 α-methyl ester (36). Yield, 0.091 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([NH:26][S:27]([CH:30]5[CH2:32][CH2:31]5)(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:33][CH3:34])=[C:24]([NH:26][S:27]([CH:30]5[CH2:31][CH2:32]5)(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(=O)(=O)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(=O)(=O)C1CC1
Yield: 8.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)cyclo propanesulfonamide (80 mg, 0.119 mmol) was hydrolyzed by lithium hydroxide (0.0109 g, 0.238 mmol), THF/Methanol/water (12/8/4 mL) to afford 5 mg (8.19% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 9.04 (s, 1H), 8.44-8.42 (d, 2H), 8.29 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.61-7.58 (m, 2H0, 7.20-7.10 (m, 4H), 5.41 (s, 2H), 3.88 (s, 3H), 0.92-0.88 (m, 4H). MS: m/z=517.8 (M+1), HPLC: 84.12% Method B.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: Ic1ccccn1
Product: CCOC(=O)c1cc2cccnc2n1-c1ccccn1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.1, starting with ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 3.2 and 2-iodopyridine. A beige-colored solid is obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.CN(C=O)C.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32](O)=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:41])[CH:37]([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32]([NH:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:41])[CH:37]([CH3:38])[CH3:39])=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2ccccc2n1-c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
DMAP (122 mg, 1.0 mmol) and EDAC (249 mg, 1.3 mmol) were added as solids to a DMF solution of 1-phenylindole-2-carboxylic acid (237 mg, 1.0 mmol in 2 ml, DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (306 mg, 1.0 mmol in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The yellow reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a colorless film (0.827 g). The film was subjected to flash chromatography on silica gel with ethyl acetate/hexanes (1:2) to yield the title product as a white foam (400 mg, 78%). TLC: (ethyl acetate/hexanes 1: 1): Rf=0.27.
Reaction SMILES: C1(C)C=CC(S([CH:10]([C@:12]2([O:23][CH2:22][C@@H:19]([O:20][CH3:21])[C@@H:16]([O:17][CH3:18])[C@@:14]2([C:24]([CH3:26])=[CH2:25])[OH:15])[OH:13])O)(=O)=O)=CC=1.[I-:28].[Na+]>CC(C)=O.C(OCC)C.CCCCC>[I:28][CH2:10][C@:12]1([O:23][CH2:22][C@@H:19]([O:20][CH3:21])[C@@H:16]([O:17][CH3:18])[C@@:14]1([C:24]([CH3:26])=[CH2:25])[OH:15])[OH:13]
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCCCC
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)CI
Yield: 88 %

Procedure:
Following the procedure described for the preparation of Example 12, starting from 0.10 g (0.25 mmol) of the compound obtained in Example 30 and 0.18 g (1.20 mmol) of sodium iodide in 3 ml of acetone at room temperature, then purification by chromatography on silica gel (eluant: diethyl ether/pentane, 1.5:1), 0.079 g (0.22 mmol) of the desired product in the form of a pale-yellow-coloured solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH:6]=[CH:5]2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1.C(Cl)Cl>>[C:20]([O:15][CH2:14][C@H:13]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:12])[CH3:16])(=[O:22])[CH3:21]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 45 °C

Procedure:
A mixture of (R)-6-chloro-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (750.0 mg, 0.002653 mol), acetic anhydride (0.325 mL, 0.00345 mol), pyridine (0.322 mL, 0.00398 mol) and methylene chloride (20 mL, 0.3 mol) was heated at 45° C. over night. The solvent was removed under reduced pressure and dried to get pure product as thick yellow oil. MS m/z=325.4 (M+H). 1H NMR (400 MHz; DMSO) δ 8.42 (d, J=8.61 Hz, 1H), 7.47 (d, J=8.61 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 6.29 (d, J=8.03 Hz, 1H), 5.34-5.29 (m, 1H), 4.28-4.20 (m, 2H), 1.94 (s, 3H), 1.40 (d, J=6.96 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:11][NH:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:10]1[CH:9]=[CH:8][N:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:13]([NH:12][CH3:11])=[O:14])=[CH:3][C:4]=12
Reactant: Brc1ccn2ccnc2c1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2ccn3ccnc3c2)c1

Procedure:
7-Bromo-imidazo-[1,2-a]-pyridine (1 eq, 0.5 mmol, 100 mg) and (3-methylamino carbonylphenyl)boronic acid (1.1 eq, 0.558 mmol, 99.9 mg) are dissolved in DME (3 ml) and water (0.8 ml) and Na2CO3 (3 eq, 1.52 mmol, 161 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.025 mmol, 17.8 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-imidazo[1,2-a]pyridine-7-yl-N-methyl-benzamide as a brown solid; [M+H]+=252
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5]([C:7]1([NH:11]C(=O)OC(C)(C)C)[CH2:10][CH2:9][CH2:8]1)=[O:6].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24].[F:1][C:2]([F:19])([F:20])[CH2:3][NH:4][C:5]([C:7]1([NH3+:11])[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CCC1
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]C1(C(=O)NCC(F)(F)F)CCC1
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 1-(2,2,2-trifluoroethylcarbamoyl)cyclobutylcarbamate (500 mg, 1.68 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (TFA, 1.0 mL) dropwise and the reaction mixture was stirred overnight. The volatiles were evaporated and the residue was triturated with pentane to give the title compound as colorless gum which was taken on to the next step without further purification (400 mg, 77%): 1H NMR (300 MHz, DMSO-d6) δ 9.14 (t, J=6.0 Hz, 1H), 8.52 (bs, 2H), 4.08-3.96 (m, 2H), 2.63-2.55 (m, 2H), 2.27-2.14 (m, 2H), 2.08-2.00 (m, 2H); ESIMS m/z 196.9 ([M+H]+); IR (thin film) 3364, 2949, 1680, 1033 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][OH:10])[C:2]=1[NH:1][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11]
Reactant: Nc1c(Cl)cccc1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To the crude (2-amino-3-chlorophenyl)methanol (1.08 g, 6.88 mmol) in CH2Cl2(15 mL) was fast dropwise added trimethylacetyl chloride (0.89 mL, 7.23 mmol), followed by DIEA (2.4 mL, 13.8 mmol) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 1 hr. Normal aqueous work-up to afford the expected product as a white solid (1.58 g, 95% yield), which was pure enough to be used in next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (s, 9 H), 3.35 (s, 2 H), 4.36 (d, J=6.29 Hz, 1 H), 7.06-7.22 (m, J=7.81, 7.81 Hz, 1 H), 7.29-7.33 (m, 2 H), 7.58 (s, 1 H); Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9](Cl)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:22]([C:14]1[C:13]([NH:12][C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[O:10])=[CH:18][C:17]([Cl:19])=[C:16]([O:20][CH3:21])[CH:15]=1)(=[O:24])[CH3:23]
Reactant: COc1cc(C(C)=O)c(N)cc1Cl
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1cc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)cc1Cl
Yield: 69 %

Procedure:
Compound 42g was synthesized from compounds 38 and 40g as a beige solid in 69% yield, according to the procedure as described for compound 42a.
Reaction SMILES: [NH2:1][C:2]1([C:15]([F:19])([F:18])[CH2:16][OH:17])[C:11]2([CH2:13][CH2:12]2)[CH2:10][O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:14])=[CH:6][CH:7]=2.[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br:14][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][CH2:10][C:11]1([CH2:13][CH2:12]1)[C:2]2([NH:1][C:29]([NH:28][C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[S:30])[C:15]([F:19])([F:18])[CH2:16][OH:17]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2
Solvent: CC(C)=O
Product: O=C(NC(=S)NC1(C(F)(F)CO)c2cc(Br)ccc2OCC12CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
Under ice cooling, to a solution of 2-(4-amino-6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-yl)-2,2-difluoroethanol (2.24 g, 6.46 mmol) in acetone (45 mL) was added benzoyl isothiocyanate (1.16 g, 7.10 mmol), and the mixture was stirred for 2 hours at room temperature and stirred for 13 hours at 40° C. After concentration, the residue was purified by silica gel chromatography (EtOAc/hexane=1:99-30:70) followed by purification using silica gel chromatography (NH-silicagel, EtOH/CHCl3=0:100-10:90) to give N-{[6-bromo-4-(1,1-difluoro-2-hydroxyethyl)-4H-spiro[chromene-3,1′-cyclopropan]-4-yl]carbamothioyl}benzamide (684 mg).