Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[N:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:24][C:22]1[CH:21]=[N:20][N:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][OH:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:10]([NH:9][CH2:8][CH:7]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:18]=2)[CH:23]=1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
The title compound can be prepared by dissolving N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenylethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD) in methanol and adding a 2:1 by mass mixture of activated carbon and iron (III) chloride (40 mol % with respect to the substrate), followed by a large excess (100-fold with respect to the substrate) of hydrazine monohydrate. The resulting mixture is stirred at 65° C. for 3 hours, then filtered, before being concentrated under reduced pressure. Trituration of the residue with petroleum ether and subsequent filtration would give the desired product as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35](B1OB(C=C)OB(C=C)O1)=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:35]=[CH2:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256 mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakis triphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassium carbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in a microwave vial (heating block) at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (168 mg>100%) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=3[N:13]=2)[CH:19]=[N:18]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1ncc2ccc(-c3cnn(CC(C)(C)O)c3)nc2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 57, 50.6 mg, 0.239 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 124, 63.6 mg, 0.239 mmol), Pd(dppf)C2•DCM (20.2 mg, 0.024 mmol), Na2CO3 (2M, 0.24 mL, 0.48 mmol) in DME (4 mL) was stirred at 140° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc and dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25-80% EtOAc/cyclohexane to give the title compound as orange semi-solid (21 mg, 28%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](C#N)=[CH:16][CH:15]=[CH:14]2.C([O-])([O-])=O.[Cs+].[Cs+].O.[CH3:30][N:31](C=O)C>>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:30]#[N:31])[CH:20]=[CH:19]2)=[O:5]
Reactant: CN(C)C=O
Reactant: O=Cc1ccccc1O
Reactant: N#Cc1cccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: N#Cc1ccc2cc(Oc3ccccc3C=O)ccc2c1

Procedure:
A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol), 6-bromo-1-cyanonaphthalene (150 mg, 0.65 mmol), and Cs2CO3 (248 mg, 0.76 mmol) in DMF (10 mL) was heated at 90° C. for 2 days, treated with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated, and the crude product was purified by column chromatography with 10% ethyl acetate/hexane to provide 40 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]([PH:10](=[O:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCOCC1.O>[C:4]1([CH2:3][CH:2]([PH:10](=[O:11])[OH:12])[NH:1][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(Cc1ccccc1)[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Temperature: 20 °C
Yield: 83.7 %

Procedure:
To a solution of 7 g (37.8 mmol) of (1-amino-2-phenylethyl)phosphinic acid in 86 ml of a mixture of dioxane and water, in the presence of one equivalent of sodium hydroxide (1.51 g), are added dropwise, at 0° C and simultaneously, a solution of 7.55 g (44.26 mmol) of benzyl chloroformate in 21 ml of dioxane and, in order to keep the pH of the reaction at about 9, a solution of 2.42 g of sodium hydroxide in 21 ml of water. At the end of the addition, the mixture is maintained at a temperature in the region of 20° C. for 2 hours. The aqueous phase is then washed with 3 times 20 ml of diethyl ether. The aqueous phase is acidified, at 0° C., with vigorous stirring, using 27 ml of 6N hydrochloric acid solution. The abundant white precipitate formed is filtered off, washed with water and dried. 12.08 g of product are recovered (yield=83.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Br)=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Nc1nc(Cl)cnc1Br
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.62 g, 7.18×10−3 mole) in absolute ethanol (2.05 ml) was added slowly to a mixture of 2-amino-3-bromo-6 chloropyrazine (1 g, 5.1×10−3 mole) and tetrakis(triphenylphospine)palladium(O) (0.334 g, 2.89×10−4 mole) in benzene (10.20 ml)/2M aqueous sodium carbonate (5.50 ml). The mixture was refluxed for 17 hrs. The cooled reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer was washed with water (2×30 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.205 g (14%), M.p. 211-214° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:14]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=3[O:23][CH3:24])[CH2:13][CH2:12][CH2:11][C:10]2=[O:25])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=1[CH:14]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH:7]=2)[C:10](=[O:25])[CH2:11][CH2:12][CH2:13]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 1-((2-bromopyridin-4-yl)methyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one (43 mg; 0.10 mmol; compound corresponding to example 36), commercially available 2-(tributylstannyl)thiazole (144 mg; 0.38 mmol), and PdCl2(PPh3)2 (7.5 mg; 0.01 mmol) in anh. THF (3 ml) was heated to 75° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 410.00 g/mol.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][C:18](C)(C)[C:19](C1C2C(=NC=C(C3C=CC4NC(=O)CSC=4C=3)N=2)NC=1)=O.Br[C:44]1[CH:45]=[CH:46][C:47]2[O:52][C:51]([CH3:54])([CH3:53])[C:50](=[O:55])[NH:49][C:48]=2[CH:56]=1>>[CH3:53][C:51]1([CH3:54])[C:50](=[O:55])[NH:49][C:48]2[CH:56]=[C:44]([C:2]3[N:3]=[C:4]4[C:10]([C:11]([C:12]5([CH3:15])[CH2:14][CH2:19][CH2:18][CH2:17][CH2:13]5)=[O:16])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)[CH:45]=[CH:46][C:47]=2[O:52]1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc4c(c3)SCC(=O)N4)nc12
Reactant: CC1(C)Oc2ccc(Br)cc2NC1=O
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc5c(c4)NC(=O)C(C)(C)O5)nc23)CCCCC1

Procedure:
Substituting (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone for 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one. MP=>300 C., (M+H)+=419. 7-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-4H-benzo[1,4]thiazin-3-one. Substituting 7-bromo-4H-benzo[1,4]thiazin-3-one for 6-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. MP=>300 C., (M+H)+=367.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][C:15]([CH3:20])([CH2:18][NH2:19])[CH2:16][NH2:17].C(N)(N)CC.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH3:3].[NH2:17][CH2:16][C:15]([CH3:20])([CH3:14])[CH2:18][NH:19][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(Cl)nc2ccccc12
Reactant: CC(C)(CN)CN
Agent: CCC(N)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(NCC(C)(C)CN)nc2ccccc12
Product: N
Yield: 45.1 %

Procedure:
A mixture of 2-chloro-4-methoxyquinoline (0.63 g, 3.25 mmol) and 2,2-dimethyl-1,3-propanediamine (2.00 g, 19.5 mmol) was stirred for 16 h at 75° C. in a sealed propanediamine (2.00 g, 19.5 mmol) was stirred for 16 h at 75° C. in a sealed NaHCO3 and ethyl acetate. The organic layer was dried (MgSO4) and concentrated onto silica, then chromatographed eluting with 5% then 10% methanol/CH2Cl2+0.5% 880 aqueous ammonia to give the title compound as a white solid (0.19 g, 23%). δH (CDCl3) 0.99 (6H, s, C(CH3)2), 2.57 (2H, s, 2′-H), 3.41 (2H, s, 4′-H), 3.96 (3H, s, OCH3), 5.98 (1H, s, 3-H), 7.12-7.93 (4H, m, ArH). MS (ES+) 260 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Br
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-fluoro-4-nitrotoluene (1.662 g, 7.102 mmol, as prepared above) in DMF (7.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.690 g, 7.11 mmol, Aldrich, used as received) in water (7.0 mL). The resulting suspension was stirred overnight at 70° C. The suspension was cooled to room temperature and the red solid was filtered, washed with acetone, and dried under vacuum to give 0.932 g (45%) of the pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ2.306 (s, 3H), 3.452 (d, 2H, J=3.9 Hz), 6.874 (s, 1H), 8.125 (s, 1H), 8.779 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:34][CH2:33][CH2:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=2)[NH:28][CH:27]=1)=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
Thionyl chloride (0.113 mL; 1.55 mmol) was added to a mixture of 3-benzylbenzoic acid (0.110 g; 0.518 mmol) in chloroform (10 mL). The reaction mixture was stirred at 65° C. for 18 hours and evaporated to dryness. The resulting residue was dissolved in chloroform (6 mL) and the solution is cooled to 0° C. A solution of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.110 g; 0.466 mmol) and triethylamine (0.363 mL; 2.59 mmol) in chloroform (6 ml) was then added and the mixture was stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) to furnish 0.154 g (76%) of 3-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Br>CS(C)=O>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1

Procedure:
As described in Example 23, 125 mg (0.43 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (Example 2), 30 mg of 60% NaH/mineral oil, and 0.1 mL of 5-bromopentanoic acid methyl ester in 15 mL of DMSO were reacted to give 80 mg of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]pentanoic acid methyl ester, after chromatography on silica (eluted with CH2Cl2→2% MeOH/CH2Cl2). This material in 5 mL of THF and 15 mL of EtOH was treated with 2 mL of 2N NaOH and the mixture stirred for 18 hours. After acidifying with 5N HCl, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in MeOH/CH2Cl2, concentrated and diluted with ether to give 80 mg (100% yield) of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]pentanoic acid, mp, 168-169° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH3:13][N:14]([CH3:15])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
7.00 g of 4-methylbenzenesulfonyl chloride was dissolved in 70 mL of methylene chloride, to which 3.59 g of dimethylamine hydrochloride was added at room temperature and 12.8 mL of triethylamine was added dropwise in an ice bath, and then this solution was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out thereof under reduced pressure to yield 6.75 g of N,N,4-trimethylbenzenesulfonamide as white solid.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([C@@H:13]2[O:21][CH2:20][C:16]3=[N:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([C@@H:13]2[O:21][CH2:20][C@:16]3([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=4[F:29])[NH:17][O:18][CH2:19][C@@H:15]3[CH2:14]2)[CH2:12][CH2:11]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: C1O[C@@H](C2CC2)C[C@H]2CON=C12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (2.97 mL, 24.1 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (1.67 g, 9.99 mmol) in toluene (150 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 1.37 mL, 11.2 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 4.24 mL, 10.6 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a white solid after azeotroping twice with dichloromethane. Yield: 2.16 g, 7.68 mmol, 77%. GCMS m/z 281 [M+]. 1H NMR (400 MHz, CDCl3) δ 7.88-7.98 (m, 1H), 6.84-6.93 (m, 1H), 6.79 (ddd, J=11.9, 8.6, 2.4 Hz, 1H), 6.34 (br s, 1H), 4.04 (br d, J=12.7 Hz, 1H), 3.83 (d, J=12.5 Hz, 1H), 3.72 (d, J=7.0 Hz, 1H), 3.54 (dd, J=6.8, 5.1 Hz, 1H), 2.99-3.08 (m, 1H), 2.86-2.95 (m, 1H), 1.99 (br dd, J=13.8, 6.8 Hz, 1H), 1.56-1.68 (m, 1H), 0.88-1.00 (m, 1H), 0.51-0.64 (m, 2H), 0.37-0.47 (m, 1H), 0.24-0.33 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7](=O)[CH3:8].Br[CH:17](C(=O)C)C(=O)C.COC(N(C)C)OC.[N+]([O-])(O)=O.[OH:36][C:37]1[CH:38]=[C:39]([NH:43][C:44]([NH2:46])=[NH:45])[CH:40]=[CH:41][CH:42]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]1[CH:8]=[CH:17][N:46]=[C:44]([NH:43][C:39]2[CH:38]=[C:37]([OH:36])[CH:42]=[CH:41][CH:40]=2)[N:45]=1
Reactant: CC(=O)C(Br)C(C)=O
Reactant: CC(=O)c1sc(N2CCOCC2)nc1C
Reactant: N=C(N)Nc1cccc(O)c1
Agent: COC(OC)N(C)C
Solvent: O=[N+]([O-])O
Product: Cc1nc(N2CCOCC2)sc1-c1ccnc(Nc2cccc(O)c2)n1

Procedure:
A solution of morpholine-4-carbonitrile (10 g, 89.19 mmol) in EtOH (65 mL) was cooled on an ice bath. Anhydrous NH3 was bubbled through the solution for 5 min, followed by hydrogen sulfide. Soon after the introduction of H2S a white precipitate was observed. After the addition of both gases for 45 min NH3 addition was stopped and H2S continued for a further 15 minutes. The resulting precipitate was collected, washed with cold water, MeOH and dried under high vacuum to afford morpholine-4-carbothioic acid amide (12.83 g). Mp. 173-174° C. 1H-NMR (DMSO-D6) δ: 3.54 (t, 4H, J=4.9 Hz, CH2), 3.70 (m, 4H, CH2), 7.46 (brs, 2H, NH2). This was converted first to 1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-ethanone with 3-bromo-pentane-2,4-dione, then with dimethoxymethyl-dimethyl-amine to 3-dimethylamino-1-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-propenone in the usual manner. The latter enaminone was condensed with N-(3-hydroxy-phenyl)-guanidine nitrate to afford the title compound as a. pale solid. Mp. 227-229 C. 1H-NMR (DMSO-D6) δ: 2.49 (s, 3H, CH3), 3.46 (t, 4H, J=4.4 Hz, CH2), 3.71 (t, 4H, J=4.4 Hz, pyrimidinyl-H), 6.34 (d, 1H, J=8.8 Hz, Ph-H), 6.91 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.03 (t, 1H, J=7.8 Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH). MS (ESI+) m/z 370.10 [M+H]+ (C18H19N5O2S requires 369.44).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])[C@H:28]([CH3:46])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:47])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])[C@H:28]([CH3:46])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:47])[CH:10]=1
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.022 g, 0.039 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% methanol in dichloromethane) to give the title compound as a white solid (0.008 g, 0.017 mmol, 44%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.67 (dd, J=4.0, 8.8 Hz, 1 H), 7.13 (d, J=10.0 Hz, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 6.94-6.87 (m, 2 H), 6.58 (d, J=6.8 Hz, 1 H), 5.77 (q, J=6.8 Hz, 1 H), 4.71-4.78 (m, 1 H), 4.51-4.12 (m, 1 H), 3.64-3.62 (m, 1 H), 3.50-3.31 (m, 5 H), 3.26-3.20 (m, 1 H), 2.96-2.84 (m, 1 H), 2.74-2.70 (m, 1 H), 2.54-2.46 (m, 1 H), 2.15-2.02 (m, 2 H), 1.99 (d, J=6.8 Hz, 3 H), 1.52 and 1.38 (d, J=6.4 and 6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30ClFN5O [M+H]+ 470.2, found 470.3.