Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](O)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1ccc(C(Cl)Cn2ccnc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 1-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane-1-ol is dissolved in 2 ml of toluene, 6 ml of thionyl chloride are added and the reaction mixture is stirred for 30 minutes at room temperature. The solvent and the thionyl chloride in excess are distilled off, the residue is dissolved in 2N NaOH, extracted with ethyl acetate, dried over Na2SO4 and evaporated to yield the compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](N)=[NH:19])=[CH:14][CH:13]=1.C(O)C.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:18]([CH2:17][O:16][C:15]2[CH:21]=[CH:22][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:19]=1
Reactant: COc1ccc(OCC(=N)N)cc1
Reactant: N#Cc1nccnc1N
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(OCc2nc(N)c3nccnc3n2)cc1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 9.8 g (0.082 mole) of 3-amino-2-pyrazinecarbonitrile and the above solution of 2-(4-methoxyphenoxy)acetamidine in absolute ethanol. Refluxing time: 2 hours. Yld: 5.5 g (24%), m.p. 238°-240° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.19 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.O.NN.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 140 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 5-methoxyisatin (10.62 g, 60 mmol) in DMSO (30 mL) was added N2H4.xH2O (hydrazine hydrate, 6 mL, 120 mmol) dropwise over 5 min (exothermic). After addition, the resulting mixture was heated at 140° C. (oil temp.) for 2 h and then cooled to rt. After diluting with H2O (30 mL), 6 M HCl (12 mL, 72 mmol) was added and the resulting mixture was stirred for 1 h at rt. Ice (30 mL) was added and the reaction mixture was stirred O/N at rt. The precipitate formed was collected by suction filtration, rinsed with H2O, then dried to give the 5-methoxyoxindole (6.523 g) as a brown solid. (about 10% impurity being the oxime from starting material 5-methoxyisatin) 1H NMR (400 MHz, d6-DMSO) 6.78 (s, 1H), 6.85 (s, 1H), 6.72-6.79 (m, 2H), 3.39 (s, 3H); ESI 164.0 [M+H]+, calcd for [C9H9NO2+H]+ 164.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2CCC(C)(C)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC(c2ccc(O)cc2)CC1
Yield: 84.8 %

Procedure:
A solution of 4-(4,4-dimethylcyclohexyl)anisole (2.76 g, 12.64 mmol), boron tribromide (4.42 mL, 15.2 mmol), in methylene chloride was stirred at room temperature overnight. The reaction mixture was treated with wet ice and diluted with methylene chloride. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was chromatographed on silica gel, using toluene/ethyl acetate (18:1), to afford the title compound (2.19 g).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25](OC4C=CC([N+]([O-])=O)=CC=4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[NH:37]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([N:37]4[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: OC1CCNC1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.20 mmol) of the compound from Example 184A and 52 mg (0.6 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 50 mg (55% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>O1CCOCC1>[CH2:16]([N:18]([CH2:19][CH2:20][NH:21][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH2:22][CH3:23])[CH3:17]
Reactant: CCN(CC)CCN
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: C1COCCO1
Product: CCN(CC)CCNC(=O)c1cc(S(C)(=O)=O)ccc1OC

Procedure:
2.3 g (0.01 mol) of 2-methoxy 5-methylsulfonylbenzoic acid, 2.9 g (0.025 mol) of N,N-diethyl ethylenediamine and 40 ml of dioxan are placed in a 100 ml balloon flask provided with a stirrer and a condenser.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.O1CCOCC1.Cl>CO>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
(3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4f (37.5 mg, 0.09 mmol) was treated with 4.0M HCl/Dioxane (2 mL, 8 mmol). Methanol was added until a clear solution is formed and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The aqueous phase was brought to pH 14 with 5N KOH and extracted with Ethyl Acetate. The organic layers were washed with brine, dried (Na2SO4), and concentrated to afford the title compound 4-M (23.3 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([CH3:19])([CH3:18])[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:18][C:9]([CH3:19])([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:3][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(c3ccccc3)C(C)(C)C(=O)Nc3nccs3)cc2)cc1
Yield: 40.3 %

Procedure:
An Emry™ process vial was charged with 3-(4-bromo-phenyl)-2,2-dimethyl-3-phenyl-N-thiazol-2-yl-propionamide (70 mg, 0.168 mmol) and 4-methoxy-phenylboronic acid (77 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), 2.0 mL of 2M K2CO3, and 1.5 mL of DMF. The reaction mixture was degassed by bubbling nitrogen through for 15 min, then sealed and exposed to microwave irradiation for 30 min at 150° C. The reaction mixture was cooled, filtered, and diluted with ethyl acetate. The organic solution was washed, dried and concentrated. The crude product was purified by preparative HPLC to give the title compound of Example 374 as a white solid (30 mg, 40%). LC/MS (m/z) 444.37 [(M+H)+]; HPLC Rt: 3.770 min. 1H NMR (400 MHz, MeOD) δ ppm 7.34-7.54 (9H, m) 7.23 (2H, t, J=7.38 Hz) 7.16 (1H, t, J=7.12 Hz) 7.02 (1H, d, J=3.56 Hz) 6.93 (2H, d, J=8.65 Hz) 4.63 (1H, s) 3.78 (3H, s) 1.40 (6H, s).
Reaction SMILES: C(S[C:6](=[O:19])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[F:27]>>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[F:27])=[O:19])=[CH:17][CH:16]=1
Reactant: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1F
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-(4-bromobenzyl)-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-fluoro-phenol.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH3:4].[OH-].[Li+].Cl.[CH3:18]O>O>[CH2:1]([O:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4])[CH3:18]
Reactant: CO
Reactant: COC(=O)c1ccc(C(C)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To the solution of methyl 4-(1-methoxyethyl)benzoate (181 mg, 0.95 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent to give 4-(1-ethoxyethyl)benzoic acid (166 mg, 97%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: OCC1=CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(COCc2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran in 100 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a mixture of 2.18 g of a 55% w/w suspension of sodium hydride in mineral oil and 100 ml of dimethylformamide. The mixture was stirred at room temperature for 60 minutes, after which 6.33 g of benzyl chloride were added. The reaction mixture was stirred for 16 hours, and then poured into 1 liter of water and extracted twice with ethyl acetate. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue, 13 g, was subjected to column chromatography through 200 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 4:100 to 5:100 by volume gave 9.40 g of the title compound as a colorless oily substance, boiling at 125°-130° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26](F)[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:49]1COCC1.O[Li].O>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:49])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 60 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (20 mg, 0.030 mmol, 1 equiv) in MeOH (2 mL) was added 10% Pd/C (6 mg, 0.006 mmol, 0.2 equiv). The reaction was then stirred under a balloon of H2 for 2 h. The reaction was then filtered through Celite eluting with MeOH. The filtrate was then concentrated in vacuo. The crude hydrogenation product was taken upon in MeOH (1.5 mL), water (1 mL0, and THF (0.5 mL) and LiOH.H2O (37 mg, 0.913 mmol, 30 equiv) was added. The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (5.2 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 8.07 (br. s., 2H), 7.97 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.08 (d, J=11.0 Hz, 1H), 6.83 (t, J=8.1 Hz, 1H), 5.79 (br. s., 1H), 4.70 (br. s., 1H), 3.82 (t, J=11.3 Hz, 1H), 2.63 (d, J=8.2 Hz, 1H), 2.39 (s, 3H), 1.94-1.57 (m, 12H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.15 (s, 9H), 1.12 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 644.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9][C:3]1[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(I)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(I)cc1CBr
Yield: 55 %

Procedure:
A mixture of 2-chloro-5-iodo-toluene (0.5 g, 1.98 mmol), N-bromosuccinimide (0.422 g, 2.35 mmol) and benzoyl peroxide (21.5 mg, 0.089 mmol) in dry CCl4 (5 mL) was stirred and heated to reflux for 3 h. After cooling, the mixture-was filtered, and the red filtrate was washed with a saturated solution of sodium thiosulfate (2×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether), to give 60 as a white solid (361 mg, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=2.4 Hz, 1H), 7.56 (dd, J=8.7, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.49 (s, 2H). MS (m/e) (positive FAB) 332.1 (M+H)+, m.p. 94-95° C.
Reaction SMILES: COC(=O)[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl-].[Na+].O>CS(C)=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:4][C:5]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)=[O:12])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)c2ccncc2)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionic acid methyl ester (14.7 g), sodium chloride (6.0 g) and water (1.9 cm3) in dimethyl sulphoxide (200 cm3) was stirred at 150° C. for 2 hours. The solution was cooled to room temperature, poured into water (600 cm3) and extracted with ethyl acetate-diethyl ether (1:1; 2×400 cm3). The extracts were dried (magnesium sulphate), filtered and concentrated to give 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone as a brown solid (10.2 g; 87%). δH (250 MHz; CDCl3) 3.79 (3 H, s, OCH3), 4.44 [2 H, s, C(O)CH2Ar], 6.88 (2 H, d, J 9, methoxyphenyl H-2), 7.16 (2 H, d, J 9, methoxyphenyl H-3), 7.77 (2 H, d, J 6, pyridyl H-3) and 8.80 (2 H, d, J 6, pyridyl H-2).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([OH:25])=O)[CH:20]=[CH:19][S:18]2.[C:28]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:27][C:2]([CH3:1])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:37][C:34]1[S:35][CH:36]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:33]=1)=[O:25])[CH:20]=[CH:19][S:18]2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Reactant: CC(C)(C)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(C)(C)C)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (150 mg, 0.388 mmol) with 4-tert-butyl-1,3-thiazol-2-amine (72 mg, 0.465 mmol) in the presence of EDCI hydrochloride (148 mg, 0.776 mmol) and DMAP (71 mg, 0.582 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 70 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 1.33 (s, 9H), 3.57 (s, 2H), 3.80 (s, 3H), 6.58 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.32-7.34 (m, 1H), 7.41 (d, J=4.5 Hz, 1H), 7.87 (d, J=16.8 Hz, 1H), 8.11 (d, J=16.5 Hz, 1H), 8.79 (d, J=3.9 Hz, 1H), 12.68 (br s, 1H); ESI-MS (m/z) 525.43 (MH)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2)(O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([NH:3][C:4]([C:7]1[C:8]2[CH2:9][C:10](=[O:16])[NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCN
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
Ethylamine (2.1 mL of 2.0 M solution in tetrahydrofuran, 4.2 mmol) was added dropwise to a suspension of 4-carboxy-2-oxindole (380 mg, 2.1 mmol) in dimethylformamide (8 mL), followed by 4-dimethylaminopyridine (385 mg, 3.15 mmol) and PyBOP (2.185 g, 4.2 mmol). The mixture was stirred at room temperature for 6 hrs. The reaction was concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and brine, dried, concentrated and recrystallized to give 280 mg (65%) of 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid ethylamide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=3[C:35]([F:38])([F:37])[F:36])[N:19]=[CH:18]4)[C:11](=[O:13])[N:12]=2)[CH2:3]1.[F:39][CH:40]([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:36][C:35]([F:38])([F:37])[C:26]1[CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=[CH:30][C:25]=1[CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:41][CH:40]([F:50])[F:39])[CH2:3]4)=[N:12][C:11]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: N[C@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N=C(N2CCC[C@H](NCC(F)F)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of DMF (1 mL) was added 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one (0.03 g, 0.05 mmol), Trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (0.02 g, 0.09 mmol) and potassium carbonate (0.014 g, 0.1 mmol). The resulting mixture was heated at 70° C. overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with MeOH/CH2Cl2 (7/93) to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].[H-].[Na+].[CH3:22]I>CS(C)=O>[Cl:1][C:2]1[C:15]2[C:10](=[C:11]([O:16][CH3:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18]
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc2c(Cl)c3c(c(O)c12)C(=O)C=CC3=O
Reaction time: 0.08 h

Procedure:
10-Chloro-8, 9-dihydroxy-1,4-anthracenedione (compound 3) (100 mg) was dissolved with stirring in dry dimethyl sulfoxide (25 ml) under a nitrogen atmosphere. Sodium hydride (80% dispersion, 28.5 mg) was added to the solution in one aliquot. The resulting dark blue solution was stirred for 5 min then methyl iodide (156 mg, 0.1 ml) was added in one lot. Stirring was continued for 10 min then another aliquot of methyl iodide (0.1 ml) was added to the mixture. After a further 5 min the dark blue solution was quenched with ice-cold phosphate buffer (pH 7) to give a red suspension which was extracted with chloroform. The combined organic extracts were dried and evaporated to a crude solid which was chromatographed on a column of silica gel 60 with chloroform as eluant. The mobile red band gave the product (compound 12) as a red solid (84 mg, 88%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:5]=[C:6]([C:15]([O:17]C)=O)[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>C(O)C>[CH3:1][NH:2][C:15]([C:6]1[S:7][C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([CH3:3])[N:5]=1)=[O:17]
Reactant: CN
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Solvent: CCO
Product: CNC(=O)c1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Methyl amine (0.5 ml) was added to a stirred solution of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (250 mg) in absolute ethanol (10 ml) at room temperature, and the mixture was stirred at room temperature for overnight. The mixture was evaporated to dryness and the residue was recrystallized from iso-propanol to give N,4-dimethyl-5-(4-pyridinyl)-thiazole-2-carboxamide (200 mg, yield 80.0%) as pale yellow needles.