Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])=[O:13].C(OCC)C>CO>[CH3:10][O:11][C:12](=[O:13])[CH:14]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)CC(Nc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
3,5-Dichloroaniline (104 g) and dimethylacetylene dicarboxylate (79 ml) were dissolved in dry methanol (100 ml) and heated under reflux for 14 h. On cooling a yellow solid crystallised out and this was collected by filtration. The mother liquors were concentrated in vacuo to leave a residue from which a second crop of product was obtained by recrystallisation from diethyl ether/60-80 petrol. The combined crops of material weighed 167.5 g (after drying at 40° C. under a pressure of 20 mmHg for 18 h). A portion of this material (105 g) was dissolved in ethyl acetate (1000 ml) and hydrogenated at 50 psi over 10% palladium on carbon catalyst (4 g) for 40 h. The catalyst was removed by filtration and the solvent evaporated under vacuum to leave a residue which was recrystallised from diethyl ether/hexane to give the title compound as a white crystalline solid (84.8 g, m.p. 66°-67° C.); δ (360 MHz, CDCl3 ) 2.88 (2H, m, CHBHC), 3.71 (3H, s, CH3), 3.78 (3H, s, CH3), 4.36 (1H, t, J=5.4 Hz, CHACHBHC), 4.71 (1H, br, s, NH), 6.51 (2H, d, J=1.8 Hz, 2-H and 6-H), 6.73 (1H, t, J=1.8 Hz, 4-H); m/e 305 (M+), 246 (100%, M-CO2CH2); Found C, 47.14; H, 4.27; N, 4.56. C12H13Cl2NO4 requires C, 47.08; H, 4.28; N, 4.58%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.Cl.[NH2:13][C@@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]([CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1nc(Cl)nc2c1SCC2)C(N)=O
Temperature: 120 °C
Yield: 74 %

Procedure:
800 mg 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 800 mg D-valinamide hydrochloride are placed in 8 ml dioxane, then 2.7 ml diisopropylethylamine are added. The reaction mixture is heated to 120° C. in the microwave for 2 hours. The residue is mixed with water. The precipitate formed is suction filtered and dried. 820 mg of the product are obtained as a powder. Analytical HPLC (method B): RT=2.64 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([Br:17])[CH:10]=1.[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:18][NH:19][C:20]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([Br:17])[CH:10]=1)=[O:21]
Reactant: NCc1ccccc1-c1ccc(CO)c(Br)c1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)NCc1ccccc1-c1ccc(CO)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 68 mg (0.23 mmol) of 2'-aminomethyl-3-bromo-1,1'-biphenyl-4-methanol (Step H) in 3 mL of dry methylene chloride and 1 mL of dry dimethylformamide under nitrogen atmosphere at 0° C. was added 0.015 mL (0.25 mmol) of methyl isocyanate. The reaction mixture was stirred for 30 minutes at 0° C. then diluted with 100 mL of ethyl acetate, washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give 71 mg (88%) of the product as a white solid which was used in the next step without further purification. 1H NMR (200 MHz, CD3 OD): δ 2.64 (s, 3H), 4.20 (s, 2H), 4.69 (s, 2H), 7.16 (m, 1H), 7.22-7.43 (m, 4H), 7.50 (d, 2 Hz, 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated for C16H17BrN2O2 349; found 349, 351 (80%).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH:22]1([C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[CH:26]=[C:27]([NH:31][C:20]3[O:8][CH2:9][C:10]4[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=4[N:19]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23]1
Reactant: Nc1cccc(C2CC2)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Yield: 73.6 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (5.8 g, 18 mmol) and 3-cyclopropyl-phenylamine (2.5 g, 19 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (4.1 g, 74%), MS (ISP) m/e=310.5 [(M+H)+].
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:7])(C)(C)C.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:32][N:19]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:12][C:8]=1[C:6]([OH:5])=[O:7]
Reactant: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)sc2C(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(C)c2nc(-c3ccccc3)sc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
4-(4-methyl-benzoylamino)-2-phenyl-thiazole-5-carboxylic acid t-butyl ester (50 mg) was dissolved in anhydrous DMF (5 mL). NaH (16 mg, 60% dispersion oil) was added. The mixture was stirred for 10 min., followed by adding iodomethane (25 μL). Stirring was continued for overnight and poured into water. The aqueous solution was extracted with methylene chloride, washed with water, brine and dried over MgSO4. Solvent was removed under reduced pressure. The residue was purified on silica gel using hexane:EtOAc 95:5. 9:1 and 85:5 as eluent. It yielded 25 mg of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2F)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
938 mg (3.07 mmol) of the compound from Example 87A were initially charged in 40 ml of dichloromethane and cooled to 0° C., and admixed with 1.28 ml (0.93 g, 9.22 mmol) of triethylamine and 0.62 g (3.07 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. It was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 1.21 g of crude product in 85% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.C(O)C.O.[BH4-].[Na+]>O1CCCC1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: -55 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
A solution of 500 mg of 11β-fluoro-7α-methylestr-4-ene-3,17-dione (B′) in 10 ml of tetrahydrofuran, 5.8 ml of ethanol and 1.15 ml of water was stirred at −55° C. with 175.6 mg of sodium borohydride for 2.5 hours. After another 351.2 mg of sodium borohydride was added, it was stirred for another 1.5 hours at −55° C., then added to ice water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. Then, it was chromatographed on silica gel with hexane/ethyl acetate. 230 mg of pure 11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one (I) with a melting point of 126.7° C. was obtained ([α]D20=+79.9° (c=0.53% in chloroform)).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[CH:8][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.O[Li].O>C1COCC1.CO.O.O>[N:1]1([C:6]2[N:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)Cc1cnc(-n2cnnn2)cn1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cnc(-n2cnnn2)cn1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl [5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetate (2.0 g, 8.5 mmol) in 60 mL of THF/MeOH/H2O (2:2:1) was added LiOH.H2O (540 mg, 12.8 mmol) portionwise and stirred for 30 minutes before diluted with 200 mL of water and washed with ether (30 mL*3). The water layer was acidified to pH=4 with diluted hydrochloric acid and extracted with EtOAc (50 mL*5). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford [5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetic acid. 1H-NMR (400 MHz, d6-DMSO) δ ppm 12.93 (brs, 1H), 10.22 (s, 1H), 9.25 (d, J=1.2 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 3.98 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: Cl
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N)C3)cccc12

Procedure:
Intermediate 26a was used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH:2]=[CH2:3].[Cl:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11]>>[Cl-:8].[CH2:1]([NH+:4]=[C:5]([NH2:7])[S:6][CH2:9][C:10](=[O:11])[N:12]([CH3:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: CN(C)C(=O)CCl
Reactant: C=CCNC(N)=S
Product: C=CC[NH+]=C(N)SCC(=O)N(C)C
Product: [Cl-]
Yield: 79 %

Procedure:
Example 1 was repeated with N-allylthiourea and 2-chloro-N,N-dimethylacetamide, affording the title compound in a yield of 79%.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]1[NH:19][CH2:18][CH2:17][S:16]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=1[CH:15]1[N:19]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:18][CH2:17][S:16]1
Reactant: Clc1cccc(Cl)c1C1NCCS1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCSC1c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
Twenty-three and five tenths (23.5) ml. of a benzene solution containing 5.9 g. of 2(2',6'-dichlorophenyl) thiazolidine was combined with 25 ml. of benzene and 2.8 g. of chloroacetyl chloride and the mixture stirred in an ice bath, while 2.6 g. of triethylamine was added dropwise. After standing for about 30 minutes the mixture was washed with water, separated, dried over magnesium sulfate and the benzene stripped off under vacuum. There was obtained a yield of 8 g. of an oil, the title compound, ND30 =1.6041.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:40]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:12]#[C:11][C:10]4[CH:9]=[N:8][CH:7]=[C:6]5[N:2]([CH3:1])[N:3]=[CH:4][C:5]=45)[CH:14]=3)=[O:42])=[CH:30][C:29]=2[C:35]([F:38])([F:36])[F:37])[CH2:23][CH2:22]1
Reactant: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CC#N
Product: CN1CCN(Cc2ccc(NC(=O)Nc3cccc(C#Cc4cncc5c4cnn5C)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
124 mg of 3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-ylethynyl)-phenylamine (Intermediate 3.1, 0.5 mmol, 1 eq.) were dissolved in 9 mL acetonitrile and treated with 163 mg of 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (0.6 mmol, 1 eq.) and 59 mg of triphosgene (0.2 mmol). The reaction mixture was stirred at rt for 4 h after which the same amounts of triphosgene and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine were added once more and stirring at rt was continued for 16 h. Extractive work-up followed by HPLC purification provided the pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24](B(CC)CC)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:24][CH3:25])=[CH:10][C:9]=2[CH3:22])=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)cc(C)c2[nH]c1=O
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C)c2[nH]c(=O)c(C(=O)OC)c(-c3ccccc3)c2c1
Temperature: 65 °C
Yield: 69.5 %

Procedure:
A mixture of 6-bromo-8-methyl-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (25 mg, 67.2 μmol, Eq: 1.00), triethylborane (134 μl, 134 μmol, Eq: 2), potassium carbonate (18.6 mg, 134 μmol, Eq: 2) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5.49 mg, 6.72 μmol, Eq: 0.1) in DMF was heated to 65° C. for 16 h in a sealed tube. Then water was added and the reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 4:1) to afford the title compound as light brown solid (15 mg). MS (ESI): 322.2 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C)C=1N.ClC1C(C#N)=C(NC2C(C)=CC=CC=2Cl)N=CN=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[N:36]1[C:46]2[C:47]3[C:39](=[C:40]([C:48](O)=[O:49])[S:41][C:42]=3[N:43]=[CH:44][N:45]=2)[NH:38][C:37]1=[O:51].[N:52]1([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=2)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[N:52]1([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([NH:65][C:48]([C:40]3[S:41][C:42]4[N:43]=[CH:44][N:45]=[C:46]5[C:47]=4[C:39]=3[NH:38][C:37](=[O:51])[N:36]5[C:30]3[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])=[O:49])=[CH:61][CH:60]=2)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cccc(Cl)c1N1C(=O)Nc2c(C(=O)O)sc3ncnc1c23
Agent: Cc1cccc(Cl)c1N
Agent: Cc1cccc(Cl)c1Nc1ncnc(Cl)c1C#N
Product: Cc1cccc(Cl)c1N1C(=O)Nc2c(C(=O)Nc3ccc(CN4CCOCC4)cc3)sc3ncnc1c23

Procedure:
Using the procedure of Example 1, 2-chloro-6-methyl-phenylamine Compound 48a was used in place of 3-chloro-4-fluoro-phenylamine Compound 1e to prepare 4-chloro-6-(2-chloro-6-methyl-phenylamino)-pyrimidine-5-carbonitrile Compound 48b. Using the procedure of Example 3, Compound 48b was used in place of 4-chloro-6-(2-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound 3b to prepare 5-(2-chloro-6-methyl-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 4&. MS 361, 363 (MH+). Using the procedure of Example 1, Compound 48c was used in place of Compound 1 and 4-morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to prepare Compound 146. MS 535, 537 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:28])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A cooled (0° C.) solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Example 4; 441 mg, 1.45 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 1.01 mL, 2.02 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.10 mL, 5.06 mmol) was added and the resulting cloudy mixture was sti f fed at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to provide rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 63% yield) as a white solid, mp 81.9-83.6° C.; FAB-HRMS m/e calcd for C13H15NCl2O3 (M+H)+303.0428, found 303.0426.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.S(Cl)([Cl:23])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:19][C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=S(Cl)Cl
Reactant: Oc1nc2ccccc2nc1-c1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1nc2ccccc2nc1-c1nc2ccccc2s1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(benzo[d]thiazol-2-yl)quinoxalin-2-ol (251 mg, 0.900 mmol) in toluene (4500 μl) was added thionyl chloride (131 μl, 1.800 mmol) followed by DMF (69.7 μl, 0.900 mmol). The green mixture was stirred at 110° C. for 3 hr. The reaction mixture was evaporated under reduced pressure and the resulting solid was diluted with CHCl3 (30-40 ml) and the insoluble solid filtered and rinsed with CHCl3. The filtrate was evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (eluted with chloroform, then dichloromethane) to provide the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([OH:18])=O)[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH2:70][N:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH2:68][CH2:69][CH2:70][N:71]3[CH2:76][CH2:75][O:74][CH2:73][CH2:72]3)=[O:18])[CH:12]=2)[CH:6]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN5CCOCC5)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)morpholine (48 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 122 mg, 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[CH2:22]([O:21][C:19]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=3)=[S:33])=[CH:3][CH:4]=2)[CH:18]=1)=[O:20])[CH3:23]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CCOC(=O)c1cc(Sc2ccc(N)cc2)nc2ccccc12
Product: CCOC(=O)c1cc(Sc2ccc(NC(=S)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc2ccccc12
Yield: 89 %

Procedure:
2-(4-aminophenylthio)-4-ethoxycarbonylquinoline (6.0 mmoles, 2.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (6.0 mmoles, 1.4 g) were reacted according to procedure C to yield 3.0 g, 89% of the title compound. Mass Spec (FD) 561. Calculated for C26H19ClF3 N3O2S2 : C, 55.56; H, 3.41; N, 7.48. Found: C, 55.38H, 3.38; N, 7.36.
Reaction SMILES: [H-].[Na+].COCCOC.Br[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1.C(N(CC)CC)C>O>[CH2:22]([NH:21][C:17]1[CH:16]=[C:15]([C:14]2[O:36][CH2:10][CH2:11][CH2:12][N:13]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(=O)NCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCC=CCCCNc1cccc(C2=NCCCO2)c1

Procedure:
To 0.4 g. of sodium hydride in 100 ml. of 1,2-dimethoxyethane is added 2.14 g. of N-(3-bromopropyl)-3-(4-tetradecenylamino)benzamide and 12 ml. of triethylamine. The turbid solution is heated to reflux for 20 hours. The solution is diluted with 100 ml. of water and cooled overnight. The solid is collected, washed with water, crystallized from cyclohexane, and recrystallized from acetonitrile to yield the product.