Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 4-[3-({4-[(5-chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (0.17 g, 0.27 mmol), 2-ethynyl pyridine (0.056 g, 0.54 mmol) and diisopropylamine (0.075 ml, 0.54 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.016 g, 0.081 mmol) and bis(triphenylphospine)palladium (II) chloride (0.038 g, 0.054 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a light brown solid (0.056 g, 35%). NMR Spectrum: (DMSOd6) 2.02 (m, 2H), 2.50 (t, 2H under DMSO), 2.72 (t, 2H), 2.84 (s, 3H), 3.01 (s, 2H), 3.28 (t, 2H under H2O), 3.94 (s, 3H), 4.20 (t, 2H), 6.23 (s, 2H), 7.21 (s, 1H), 7.32 (s, 1H), 7.45 (dd, 1H), 7.68 (d, 1H), 7.86 (m, 2H), 8.35 (s, 1H), 8.64 (d, 1H), 9.54 (s, 1H). Mass Spectrum: M+H+ 601 and M+H− 599.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH:6]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1.[OH-].[Na+].[OH-].[K+]>C1(C)C=CC=CC=1>[ClH:3].[OH:5][CH:6]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:1]2=[O:2])[CH2:10][CH2:9]1
Reactant: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccccc2)CC1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC(N2CCN(c3ccccc3)C2=O)CC1
Product: Cl
Reaction time: 20 h

Procedure:
With vigorous stirring, a solution of 117 ml of a 20% phosgene solution in toluene is added dropwise at a reaction temperature of 5° to 10° C. to an emulsion of 10 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-(2-anilino-ethylamino)-piperidine in 60 ml of toluene and 37.5 ml of a 3 N aqueous sodium hydroxide solution over 11/4 hours. Thereafter 35.5 ml of a 6 N aqueous potassium hydroxide solution are added dropwise at the same reaction temperature in the course of half an hour. Stirring is continued for 30 minutes at 5° to 10° C. and for 20 hours at room temperature. The reaction mixture is filtered with suction and the crystalline residue is treated with toluene. Recrystallisation from isopropanol yields 1-{1-[2-hydroxy-3-(2-methoxy-phenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride in the form of white crystals with a melting point of 185°-187° C. The salt can be converted into the free compound for example by treatment with an aqueous sodium hydroxide solution.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:30][C:29]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:28][C:9]=3[N:10]3[CH2:17][C:16](=O)[N:15]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.Cl.CO>C1COCC1>[CH:1]1([C:7]2[C:8]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:14][C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN1Cc2ccccc2-c2c(C3CCCCC3)c3sc(C(=O)OC(C)(C)C)cc3n2CC1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3sc(C(=O)O)cc32)-c2ccccc2C1
Reaction time: 0.05 h

Procedure:
A solution of tert-butyl 13-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylate (1 eq., prepared as described in Example 1, Step 5) in dry THF (0.14 M) was treated with borane-dimethylsulfide complex (20 eq., 2 M solution in THF) overnight at RT. A solution of HCl in methanol (40 eq., 1.25 M) was added to the reaction mixture, which was then heated to reflux for 1 h. All volatiles were evaporated in vacuo and the residual material was subjected to RP-HPLC purification (column: Waters XTERRA PREP MS C18, 10 μm; solvents: A: water+0.1% trifluoroacetic acid; B: MeCN+0.1% trifluoroacetic acid; 25% B in A isocratic for 3 min, linear to 20% A in B in 12 min) afforded the title compound after lyophilisation as a colourless powder (33%). 1H-NMR (500 MHz, DMSO-d6, 330 K, δ) 7.91 (s, 1H), 7.63 (d, J 7.1, 1H), 7.52-7.46 (m, 2H), 7.37 (d, J 6.3, 1H), 4.40 (dd, J 15.3, 4.9, 1H), 3.86 (d, J 13.9, 1H), 3.70-3.10 (m, 4H, hidden by the H2O signal), 3.05 (d, J 13.9, 1H), 3.04-2.84 (m, 2H), 2.84 (m, 6H), 2.69-2.60 (m, 1H) 2.55-2.50 (m, 1H, partially hidden by the DMSO signal), 2.02-1.09 (m, 10H). MS (ES+) m/z: 452 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][C@@H:19]([CH2:23][OH:24])[N:20]([CH2:37][C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN[C@H](CO)C3)cc12
Reactant: CN(C)C(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)[C@H](CO)C3)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of Example 260H (150 mg, 0.352 mmol) in N,N-dimethylformamide (1.8 mL) was added N-ethyl-N-isopropylpropan-2-amine (227 mg, 1.759 mmol) and 2-chloro-N,N-dimethylacetamide (39.9 μL, 0.387 mmol). The mixture was stirred for 3 days at room temperature and for 2 hours at 70° C., and partitioned between water and ethyl acetate (three times). The extracts were dried over sodium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-8% methanol/dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.18 (d, J=5.0 Hz, 1H), 7.31-7.16 (m, 3H), 7.02 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.74 (s, 3H), 3.60-3.27 (m, 6H), 3.33 (s, 3H), 3.02 (s, 3H), 2.93 (dd, J=11.1, 5.7 Hz, 1H), 2.81 (s, 3H), 2.48-2.32 (m, 2H); MS (ESI+) m/z 439.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:6]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C62(ii) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in N,N-dimethylacetamide (1.0 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.115 g, 0.33 mmol) produced in Example C63(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (50 μL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (80 mg, 44%) as colorless crystals.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:14]1([CH2:21][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O:23]1[CH2:24][CH2:25][N:20]([CH2:15][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:11])[CH2:21][CH2:22]1
Reactant: C1CCNCC1
Reactant: Oc1cccc2ccccc12
Reactant: C1COCCN1
Agent: C=O
Product: Oc1c(CN2CCCCC2)ccc2ccccc12
Product: Oc1c(CN2CCOCC2)ccc2ccccc12

Procedure:
Anon. (USA) (Res. Discl., 236, 380 (Ger), 1983) discloses a Mannich reaction of 1-naphthol with formalin and piperidine or morpholine to yield 2-(piperidinomethyl)-1-naphthol or 2-(morpholinomethyl)-1-naphthol, respectively. These compounds were subjected to hydrogenolysis (Pd/C) whereby 2-methyl-1-naphthol was produced
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(OC(=O)[NH:50][CH2:51][CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][C:55]=1[C:61]1[N:62]([CH3:67])[N:63]=[CH:64][C:65]=1[Cl:66])(C)(C)C.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[F:72][C:71]([F:74])([F:73])[C:69]([OH:75])=[O:70].[NH2:50][CH2:51][CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([NH:60][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)=[CH:56][C:55]=1[C:61]1[N:62]([CH3:67])[N:63]=[CH:64][C:65]=1[Cl:66]
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)cc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 4-methoxy-3-methylbenzoic acid (10 mg, 59 μmol), HATU (23 mg, 1.1 eq), and Et3N (11 mg, 1.5 eq.) in DCM (1 mL) was stirred 20 min at 40° C. {2-[4-Amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester (18 mg, 50 μmol) was added into the acid-HATU solution, and the reaction was stirred overnight at 40 C. The reaction was treated with TFA (˜0.2 mL) and heated to ˜90° C. for 1 h. The reaction was filtered through a strong cation exchange resin to remove impurity, TFA, and tetramethyl urea, and purified by prep-HPLC: Waters YMC ODS-A™ C18 column (5μ, 4.6×50 mm), 5% v/v CH3CN (containing 0.05% v/v TFA) in H2O (containing 0.05% v/v TFA) gradient to 60% V/V CH3CN in H2O, 20 mL/min. N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamide trifluoroacetate (14 mg, 69%) was obtained as a white powder. LCMS m/z (%)=415.3 (M+H 35Cl, 100), 417.3 (M+H 37Cl, 31). 1H NMR (400 MHz, DMSO-d6) δ: 10.1 (s, 1H), 7.93 (dd, J=2.5 and 8.8 Hz, 1H), 7.91-7.82 (m, 4H), 7.79 (bs, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.65 (s, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.19 (m, 2H), 3.86 (s, 3H), 3.67 (s, 3H), 3.16 (m, 2H), 2.21 (s, 3H).
Reaction SMILES: C([Li])CCC.[Cl-].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][PH3+].[CH:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=O>CCCCCC.O1CCCC1.O>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:19]/[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: [PH3+]Cc1ccc2ccccc2n1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
2.5M Butyl lithium in hexane (8.8 ml) is added over 5 minutes to a stirred solution of quinolin-2-ylmethylphosphonium chloride (9.66 g, 22 mmol) in dry tetrahydrofuran (250 ml) at -75° C. The mixture is stirred for 1 hour at -75° C. then a solution of methyl 3-formylbenzoate (3.28 g, 20 mmol) in tetrahydrofuran (25 ml) is added dropwise over 10 minutes. After stirring for a further 30 minutes at -75° C., the mixture is warmed to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried and evaporated and the residue is purified by chromatography on silica eluting with ethyl acetate-hexane (1:3).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O.[ClH:26]>C(O)(=O)C>[Cl:26][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][C:10]([Cl:18])=[CH:9][CH:8]=3)[CH:13]([C:15]([OH:17])=[O:16])[C:14]=2[CH:1]=1
Reactant: Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Product: O=C(O)C1c2cc(Cl)ccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a suspension of 10 g of xanthene-9-carboxylic acid and 14 g of N-chlorosuccinimide in 80 mL of acetic acid was added with stirring dropwise 2.0 mL of conc. HCl over a period of 5 minutes. The mixture was stirred at room temperature for 12 hours and quenched by the addition of 150 mL of water. The precipitated solid was removed by filtration, rinsed with water, and dried in air to give 12.6 g (100%) of the crude carboxylic acid as a white solid. Recrystallization from MeOH--EtOAc (2:1) gave 6.98 g (55.2%) of the pure 2,7-dichloroxanthene-9-carboxylic acid as colorless small needles, m.p. 273°-275° C. (dec.); IR (KBr): 2970 (b, OH), 1695 (C=O) cm-1 ; 1H NMR (DMSO-d6): δ 5.01 s, 1H, CH), 7.05-7.50 (m, 6H, aryl).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15](OC)=[O:16])=[O:12].N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C1COCC1.CCOC(C)=O>[O:16]=[C:15]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(=O)n(-c2ccccc2)[nH]1
Temperature: 67 °C
Yield: 34.7 %

Procedure:
Phenylhydrazine (0.5 g; 4.62 mmol), acetylenedicarboxylic acid dimethyl ester (0.66 g; 4.62 mmol) and 4-toluenesulfonic acid pyridine salt (1.16 g; 4.62 mmol) were dissolved in 7 ml of dry THF under nitrogen atmosphere and the solution was stirred for 2 h at RT after which 7 ml of 10% HCl (g) in EtOAc was added and the mixture heated at 67° C. for 5 h. The reaction mixture evaporated to dryness and 6 ml of DCM added to the residue. The organic phase was washed with 8 ml of water and the combined water phases were extracted with 2×6 ml of DCM. The combined organic phases were once more washed with 12 ml of water, dried over Na2SO4, filtered and evaporated to dryness to give 0.35 g of the product which was used as such without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]([O:31][C:32](=O)[CH:33](C1C=CC=CC=1)[OH:34])(=[O:30])[CH3:29].C(N(CC)CC)C>O1CCOCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:33]([CH2:32][O:31][C:28](=[O:30])[CH3:29])=[O:34])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: CC(=O)OC(=O)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
This material was prepared according to the procedure described in Example 78(a) using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.36 g, 0.9 mmol), O-acetyl mandelic acid (0.41 mL, 1.8 mmol, Heico Chemicals, Inc.) and triethylamine (0.25 mL, 1.8 mmol) in dioxane (3 mL). Purification by silica gel chromatography (3:1 hexanes: EtOAc) provided the title compound as a light-yellow foam. MS (ESI, pos. ion) m/z: 565 (M+1). Mp: 118.6–138.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[CH2:14][S:15]CC1C=CC(OC)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[CH2:14][SH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CSCC2NC(=O)C2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1C(=O)NC1CS
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To a solution of 335 mg (0.95 mmole) of 3-t-butoxycarbonylamino-4-oxo-2-(p-methoxybenzylthiomethyl)azetidine in 5 ml of methanol and 20 ml of methylene chloride is added 1.7 g (5.3 mmole) of mercuric acetate. The mixture is stirred 24 hours under argon, diluted with excess ether and the precipitated mercury adduct filtered and washed well with ether. The mercury complex is suspended in water, layered with ethyl acetate and hydrogen sulfide gas is passed through the mixture for 1 hour. The mercuric sulfide is removed by filtration, the ethyl acetate layer is separated and washed with brine, dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with 1:1 ethyl acetate-hexane gives 122 mg (55%) of the crystalline title product.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].O.[CH3:18][Mg+].[Br-]>C(Cl)Cl.C(OCC)C>[F:1][C:2]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C@@H:4]([NH:5][S@@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH3:18]
Reactant: C[Mg+]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cccc(F)c1F
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.800 g, 3.26 mmol) in DCM (32.6 mL), cooled to 0° C. (water/icebath) under N2, was added 3M MeMgBr (4.35 mL, 13.05 mmol) in diethyl ether. Reaction mixture allowed to stir for 30 min at 0° C. Then gradually allowed to warm to room temperature and stirred for 30 min at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried with MgSO4, filtered and concentrated to afford (R)—N—((S)-1-(2,3-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.7868 g, 3.01 mmol, 92% yield) as yellow solid. MS m/z 262.0 (M+H)+; Rt-0.70 min.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:3].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)[CH3:1]
Reactant: CC(C)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc2c(c1)CCN2
Reaction time: 4 h
Yield: 102.5 %

Procedure:
To a cooled solution of indole (D17, 0.60 g, 3.75 mmol) in glacial acetic acid (12 ml) was added sodium cyanoborohydride (1.20 g, 19.1 mmol) in portions. The mixture was stirred under argon for 4 h, then diluted with water and basified with 10% aqueous sodium hydroxide. The mixture was extracted with dichloromethane and the extract was dried and evaporated. After combining with material from a previous experiment (from 0.14 g indole) the crude product was chromatographed on silica gel eluted with diethyl ether to give the title compound (0.62 g, 84%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45](C(Cl)=O)=[C:38]2[N:37]=1.O>C1COCC1.CCOC(C)=O>[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45]([C:4](=[O:3])[CH2:5][C:6]3[N:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]4=[N:8][C:7]=3[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:38]2[N:37]=1
Reactant: CCOC(=O)Cc1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Reactant: Cc1cc(C)n2ncc(C(=O)Cl)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To a magnetically stirred solution of [2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13c (0.075 g, 0.231 mmol) in THF (3.0 mL) at −78° C. under Ar atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (0.508 mL, 0.5M, 0.254 mmol). The reaction mixture was stirred for 15 min at −78° C., then a THF solution of 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.053 g, 0.254 mmol) was added. After an additional 60 min at −78° C., water (20 mL) was added, and the reaction mixture was warmed to room temperature. Water was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude alkylated product. The crude adduct was dissolved in acetic acid (HOAc) (1 mL) and 12 N HCl (1 mL). The reaction mixture refluxed for 2 h. The mixture was cooled to room temperature and treated with aq Na2CO3 solution until basic. The aqueous solution was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.02 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.62 (s, 3H), 2.82 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 8.62 (s, 1H). Mass spectrum m/e 426 (M+).