Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl.O>[Cl:16][CH2:17][CH2:18][C:19]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:20]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)Nc1cccc(F)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-fluoroaniline (20 g, 0.180 mol) in dichloromethane (100 mL) was added triethylamine (21.816 g, 0.216 mol) and 3-chloropropanoyl chloride (17.18 mL, 0.180 mol) under cooling condition (0° C.) with constant stirring. Reaction mass was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (d, J=10.4 Hz, 1H), 7.42 (bs, 1H), 7.29-7.24 (dd, J=14.8 Hz, 8.0 Hz, 1H), 7.15-7.13 (d, J=8.0 Hz, 1H), 6.84-6.81 (t, J=6.8 Hz, 1H), 3.89-3.86 (t, J=6.4 Hz, 2H), 2.83-2.80 (t, J=6.4 Hz, 2H). MS (M+1): 201.9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[N:34]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:43][CH:44]=3)[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Nc2ccc(CCN3CCOCC3)cc2)ncn1

Procedure:
A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:4][CH:3]=1.[F:25][C:26]1[C:39]([N:40]=[C:41]=S)=[C:38]([F:43])[CH:37]=[CH:36][C:27]=1[CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CC(C)N=C=NC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[C:11]([O:19][CH2:20][CH:21]([F:22])[F:23])=[CH:12][C:13]3[N:17]([CH3:18])[C:41]([NH:40][C:39]4[C:38]([F:43])=[CH:37][CH:36]=[C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=4[F:25])=[N:16][C:14]=3[CH:15]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(F)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound is prepared from N-(4-bromophenyl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzamide and N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1g.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CC=C(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 111.8 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min and treated with 2 g (0.01 mole) 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were combined, dried and concentrated in vacuo to yield 4.5 g of orange-yellow oil which solidified when cooled to -78° C. Recrystallization from isopropyl ether after charcoaling yielded 2.6 g (65%) of fine white crystals, m.p. 100°-102° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:15])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=1.[F:16][C:17](=[C:21]([F:23])[F:22])[CH2:18][CH2:19][OH:20]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]=[C:5]([NH:6][C:2](=[O:3])[CH3:1])[C:4]([O:20][CH2:19][CH2:18][C:17]([F:16])=[C:21]([F:23])[F:22])=[O:15])=[CH:13][CH:12]=1
Reactant: OCCC(F)=C(F)F
Reactant: CC1=NC(=Cc2ccc(F)cc2)C(=O)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NC(=Cc1ccc(F)cc1)C(=O)OCCC(F)=C(F)F
Yield: 49.1 %

Procedure:
8.2 g (40 mmol) of 2-methyl-4-(4-fluorobenzylidene)-oxazol-5-one of Example (II-1) in 100 ml of toluene are heated overnight under reflux with 6.3 g (50 mmol) of 3,4,4-trifluorobut-3-enol, with the addition of 200 mg of 4-dimethylaminopyridine. After cooling, the solution is washed with water and concentrated under reduced pressure and the brown solid is chromatographed over silica gel using the system chloroform/ethyl acetate (4:1). 6.5 g (Yield 49% of theory) of 3,4,4-trifluorobut-3-enyl 3-(4-fluorophenyl)-2-acetylamino-prop-2-enoate of mp.: 116° are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[C:13](=O)[CH:14](Br)[CH3:15])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([CH3:15])=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:18])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1nc2c(N)cccn2c1C
Yield: 33.8 %

Procedure:
A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g, 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by filtration and washed with dichloromethane:methanol (10:1). The filtrate and washings were combined the solvents were removed under reduced pressure. The oily residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g (34%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3csc(-c4ccccc4)n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-phenyl-1,3-thiazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 420.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1.B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[N:6][C:7](=[O:16])[C:8](=[O:15])[N:9]=2)[CH:4]=1
Reactant: COc1cc2c(cc1OC)=NC(=O)C(=O)N=2
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N=c2cc(O)c(O)cc2=NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
To a suspension of 6,7-dimethoxy-2,3-quinoxalinedione (45) (222 mg, 1.0 mmol) in 2 mL of methylene dichloride was added 5 mL of a solution of boron tribromide in methylene dichloride (1 M, Aldrich). The resulting mixture was stirred at room temperature for 24 hr. The mixture was then poured into ice-water (10 g) to form a suspension. Aquous sodium hydroxide (20%, 10 mL) was added to the suspension to form a red solution. The solution was acidified with 6 N HCl (10 mL) to pH=1. The suspension was centrifuged, washed with methanol, and dried in vacuo, giving 170 mg (88%) of the product as a brown solid; mp>350° C.; 1H NMR (DMSO-d6, 300 MHz) δ 6.541 (s, 2H), 8.989 (s, 2H), 11.543 (s, 2H). EIMS m/e 194 (100, M+). (HPLC>99%).
Reaction SMILES: Br.Br[C:3]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[N:6]=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.ClCCl.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:3]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[N:6]=[CH:5][CH:4]=1
Reactant: Brc1ccnc2c1CCNC2
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Br
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2c1CCNC2
Temperature: 70 °C
Reaction time: 0.01 h
Yield: 66.9 %

Procedure:
A pressure vessel was charged with 4-bromo-5,6,7,8-tetrahydro-1,7-naphthyridine hydrobromide (331 mg, 1.126 mmol), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (488 mg, 2.219 mmol), cesium carbonate, 99.9% (metal basis) (0.275 mL, 3.44 mmol), and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (ii) dichloromethane adduct (86 mg, 0.105 mmol). Dioxane (2 mL) and water (0.4 mL) were added, and argon was streamed into the vessel for about 20 seconds. The mixture was stirred in a 70° C. oil bath for two hours, then diluted with CH2Cl2 and washed with H2O. The layers were separated and the water layer was extracted with another portion of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Combiflash, 40 gram Redisep gold column), eluting with 0-100% (3:1 EtoAc/EtOH with 2% NH4OH in heptane) to obtain 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (232 mg, 0.753 mmol, 66.8% yield) as a brown viscous oil. [M+H]+=309.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: CS(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with methanesulfonyl chloride to obtain the desired product. 1H NMR: (500 MHz, CDCl3): δ=7.38-7.37 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.20-7.0 (q, 1H), 6.68 (s, 1H, br), 6.15-6.12 (q, 1H), 5.65 (s, 1H, br), 2.95 (s, 3H); m/z=441 [M−1]−.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.CCN(CC)CC.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:19]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:7]1=[O:11])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NCc2cc(I)ccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)N1Cc2cc(I)ccc2C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-iodo-2,3-dihydroisoindol-1-one (3 g) in DMF (60 mL), were added N,N-dimethylaminopyridine (DMAP: 14 mg), Et3N (4.84 mL) and tert-butyl-diphenylsilyl chloride (9.0 mL). The mixture was stirred at 50° C. for 2 h. After cooling, saturated NaHCO3 aq. was added into the reaction mixture. Then it was extracted with EtOAc. The organic layer was washed with water and brine, then was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The trituration with Et2O followed by filtration gave compound aa2-1 (2.78 g) as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(Cc2ccccc2)CC1

Procedure:
18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylamine hydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol are stirred for 8 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][CH2:70][NH2:71])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.CO>[C:56]([O:60][C:61]([N:63]1[CH2:64][CH2:65][N:66]([CH2:69][CH2:70][NH:71][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (505 mg, 1 mmol) in DMF (10 mL) was added HOBt (202 mg, 1.3 eq.), EDAC.HCl (288 mg, 1.5 eq.) and TEA (302 mg, 3 eq.). After stirring at rt for 30 mins, to the mixture was added 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (298 mg, 1.3 eq.). After stirring at 40° C. for overnight, the reaction was diluted with methanol (2 mL), the precipitate was collected by vacuum filtration, washed with methanol, water and dried to give 700 mg of 4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:20]=[CH:19][C:13]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:12][CH:11]=1.Cl[C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:17]([C:16]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:30][O:15][C:14]=1[C:13]1[CH:19]=[CH:20][C:10]([C:9]([F:21])([F:22])[F:8])=[CH:11][CH:12]=1)#[N:18]
Reactant: N#CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1C#N
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Triethylamine (0.98 mL, 7.0 mmol) was added to a −5° C. solution of 4-trifluoromethylbenzoylacetonitrile (1.5 g, 7.0 mmol) in ethanol (15 mL) and the mixture was stirred for 20 minutes. A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (1.06 g, 7.0 mmol) in ethanol (5 mL) was added to the reaction over 15 minutes. After stirring at room temperature for 72 hours, the cream-colored solid which formed was collected by filtration, washed with cold water and dried in vacuo to obtain ethyl 4-cyano-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (1.84 g, 5.93 mmol).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([F:40])[CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][C:35]=1[F:40]
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (49 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (80 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H), 7.40-6.90 (m, 3H), 5.36 (m, 1H), 4.82 (m, 1H), 4.65 (m, 1H), 4.12 (m, 1H), 3.90-3.18 (m, 8H), 3.04-2.89 (m, 2H). 1.95 (m, 1H), 1.57 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 551.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([NH2:26])[CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[Cl:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:34][CH2:35][S:36]([NH:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:33])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:21]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC[C@H](N)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC[C@H](NS(=O)(=O)CCl)C2)n1
Yield: 57 %

Procedure:
Reaction of (3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinamine (Example 46) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2 gave chloro-N-{(3S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-piperidinyl}methanesulfonamide in 57% yield: mp (MeOH) 166-168° C.; 1H NMR (DMSO-d6) (rotamers) δ7.99 (br, 1H), 7.98 and 7.88 (2d, J=8.5, 8.4 Hz, 1H), 7.69 and 7.68 (2t, JHF=52.9 Hz, 1H), 7.41 and 7.37 (2t, J=8.1, 8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.98-4.88 (m, 2H), 4.55-4.52 and 4.37-4.23 (2m, 2H), 3.97 (s, 3H), 3.80 (m, 4H), 3.69 (m, 4H), 3.45-3.11 (m, 3H), 1.99 (br, 1H), 1.83-1.80 (m, 1H), 1.64-1.48 (m, 2H); Anal. Calcd. for C22H27ClF2N8O4S.0.5H2O: C, 45.4; H, 4.85; N, 19.25. Found: C, 45.4; H, 4.8; N, 19.2%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9](O)=O.S(Cl)(Cl)=[O:13]>>[O:13]=[C:8]1[CH2:9][C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1cccs1
Product: O=C1CCc2sccc2C1

Procedure:
4-(2-Thienyl)butyric acid was reacted with thionyl chloride and stannic chloride to provide 5-oxo-4,5,6,7-tetrahydrobenzothiophene, which upon reaction with hydrazine and sodium hyroxide gave 4,5,6,7-tetrahydrobenzothiophene. A solution of 13.3 g of 4,5,6,7-tetrahydrobenzothiophene in 150 ml of dichloromethane was added dropwise to a stirred suspension of 13.1 g of ethyl oxalyl chloride and 14.0 g of aluminum chloride in 200 ml of dichloromethane. The reaction mixture was stirred for twelve hours at 25° C. following the addition. The reaction mixture was poured into 500 g of ice and then the organic layer was separated, dried, and the solvent was removed by evaporation to give 19.2 g of ethyl α-oxo-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=1[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(N)cccc1Oc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(N)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
The product of example 2a above, 2-phenoxy-6-aminobenzonitrile, (1.5 g, 7.14 mmol) was dissolved in dry tetrahydrofuran (50 mL) and stirred under argon in a room temperature water bath. Lithium aluminum hydride (0.53 g, 14.0 mmol) was added in portions over 10 minutes. The reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by quenching by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0–3% methanol in methylene chloride gave the title compound as a white amorphous solid. Recrystallization from carbon tetrachloride, hexane gave a white crystalline solid. mp 69–71° C.