Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:42][CH:43]1[CH2:45][CH2:44]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C>O1CCCC1>[CH:43]1([CH2:42][N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:45][CH2:44]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (329) (580 mg, crude) in tetrahydrofuran (30 mL) was added 1N aq.HCl (6 mL) at room temperature and stirring was continued for 1 h (TLC; 100% ethyl acetate/UV/SiO2, Rf=0.2). Tetrahydrofuran was removed in vacuo and the crude mass was dissolved in ethyl acetate (50 mL) and washed with NaHCO3 solution (10 mL), water (20 mL) and brine (20 mL); The organic phase was dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (330) (390 mg, 94% two steps) as an off-white sticky solid.
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].C([Li])(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1.CCCCC>[OH:12][C:3]1[N:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1cc(C(F)(F)F)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 122.9 %

Procedure:
3-Bromo-5-(trifluoromethyl)pyridin-2-ol (8.20 g, 31.2 mmol) was added in small portions to a suspension of sodium hydride (0.8575 g, 33.94 mmol) in anhydrous THF (76 mL) at room temperature. After complete addition, the reaction mixture was cooled to −78° C. and treated with a 1.7 M solution of tert-butyllithium in pentane (40.0 mL) which was added dropwise via a syringe over a period of 15 min. After stirring for 5 min, anhydrous DMF (8.16 mL, 105 mmol) was added slowly while maintaining the temperature below −50° C. The reaction mixture was then stirred overnight allowing it to warm to room temperature. The resulting light brown mixture was quenched by addition of a saturated NH4Cl solution. The pH of the solution was adjusted to 9-10 by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc four times. The combined extracts were dried (MgSO4), filtered and concentrated to provide a brown solid crude product (7.33 g, >100% crude yield). MS calculated for C7H4F3NO2 (M+H)+192; found 192.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:18]([O-:21])([OH:20])=[O:19].S(Cl)([Cl:24])=O>CN(C)C=O>[C:1]([C:5]1[C:6]([N+:18]([O-:21])=[O:19])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([Cl:24])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Cl)c([N+](=O)[O-])c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C(=O)O)c([N+](=O)[O-])c(C(C)(C)C)c1

Procedure:
3,5-Di-t-butyl-2-nitrobenzoyl chloride was prepared by nitration of 3,5-di-t-butylbenzoic acid 46.86 grams (0.20 mol) with 90% nitric acid (150 ml, d=1.5) to give 3,5-di-t-butyl-2-nitrobenzoic acid (54.6 grams) followedby treatment with thionyl chloride (250 ml) with dimethylformamide (1 ml).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].C(N(CC)C(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[I:1])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CO)c(I)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cc1I
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution of (2-iodo-4-nitrophenyl)methanol (6.01 g, 21.5 mmol) in methylene chloride (50 mL) was added N,N-diisopropylethylamine (7.50 mL, 43.1 mmol) and methanesulfonyl chloride (1.83 mL, 23.7 mmol) at 0° C. The reaction solution was stirred at same temperature for 2 hours. The reaction was quenched with water, and aqueous layer was extracted with DCM once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated The crude product was purified by flash column chromatography to give the desired product (6.15 g, 80%). LCMS calculated for C8H91NO5S (M+H)+: m/z=358.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCCN1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCOC1=O

Procedure:
The 3-(2-hydroxyethyl)-2-oxazolidinone (Frinton Laboratories, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound which was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12].[I-:13].[Na+].Cl.O>C(#N)C>[I:13][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: [I-]
Reactant: N#Cc1cc2sccc2nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc2sccc2nc1I

Procedure:
A solution of 5 g of 5-chlorothieno[3,2-b]pyridine-6-carbonitrile, 10 g of sodium iodide and 1 ml of concentrated hydrochloric acid in 70 ml of acetonitrile was heated at reflux for 65 hours. The mixture was then poured into water and the resulting solid was separated by filtration. The solid was recrystallized from acetone to give 5-iodothieno[3,2-b]pyridine-6-carbonitrile as white needles melting at about 190°-191° C.
Reaction SMILES: C([Mg]Br)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH:14]([F:16])[F:15].CN(C)[CH:19]=[O:20].O>C1COCC1>[F:15][CH:14]([F:16])[C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:19]=[O:20]
Reactant: Fc1ccc(Br)c(C(F)F)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(F)cc1C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Isopropyl magnesium bromide (30 mL, 1M in THF, 30 mmol) was added dropwise to an ice-cooled solution of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (44; 6 g, 26.7 mmol) in THF (100 mL). The reaction mixture was then allowed to warm to room temperature and stirred for 3 hr. Dimethylformamide (3.5 ml, 45.2 mmol) was added and the reaction stirred for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-(difluoromethyl)-4-fluorobenzaldehyde 45 (3.2 g, 68.5%)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)[N:6]=1.Cl[C:27]([O:29][CH3:30])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[NH2:20][C:18]1[C:17]([NH:21][C:27](=[O:28])[O:29][CH3:30])=[CH:16][N:15]=[C:14]([N:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[N:6]2)[N:19]=1
Reactant: COC(=O)Cl
Reactant: Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 330 mg (0.98 mmol) of the compound from example 12A were initially charged in pyridine (12 ml), the mixture was cooled to 0° C. and 84 μl (108 mmol) of methyl chloroformate were then added dropwise. The reaction mixture was stirred further at RT overnight, and ethyl acetate was then added. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was separated by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient), giving 241 mg (62% of theory) of the target compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Na+].[C:23](C1NC=CN=1)(=[O:25])[CH3:24].Cl>C1COCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([C:23](=[O:25])[CH3:24])[C:9]#[N:10])[CH:7]=1
Reactant: CC(=O)c1ncc[nH]1
Reactant: COc1c(CC#N)cc(F)cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(OCc2ccccc2)cc(F)cc1C(C#N)C(C)=O
Temperature: 40 °C
Yield: 80 %

Procedure:
A solution of {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol) in THF (60 mL) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 1.64 g, 41 mmol) was added followed by acetylimidazole (3.2 g, 29.3 mmol). The mixture was heated to 40° C. for 15 min before cooling to rt. Water was added, and this mixture was acidified with 1 N HCl (45 mL). Ethyl acetate was added and the layers were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 2-{5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}-3-oxobutanenitrile as a colorless oil (4.9 g, 15.6 mmol, 80% yield). 1H NMR (400 MHz, CDCl3): (mixture of tautomers) δ 9.70 (s, 0.2H), 7.42-7.33 (m, 5H), 6.82 (dd, 0.2H), 6.75 (dd, 0.8H) 6.69-6.64 (m, 1H), 5.09 (s, 2H), 4.90 (s, 0.8H), 3.89 (s, 2.1H), 3.83 (s, 0.9H), 2.38 (s, 0.9H), 2.29 (s, 2.11H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].C([Li])CCC.[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]>O1CCCC1.O>[CH3:12][O:11][C:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH:19]([CH3:21])[CH3:20]
Reactant: COc1c(C)c(C)cc(C)c1Br
Reactant: CC(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)cc(C)c1C(O)(c1ccccc1)C(C)C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of 2-bromo-3,5,6-trimethylanisole (3.0 g, 13.1 mmol) in tetrahydrofuran (20 ml) was cooled to -78° C. and n-butyllitium (1.6M solution in hexane, 8.2 ml, 13.1 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes. Then a solution of isobutyrylbenzene (1.94 g, 13.1 mmol) in tetrahydrofuran (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was diluted with water and the product was extracted with isopropyl ether. The extract was washed with water, dried and then concentrated. The residue was crystallized from hexane to obtain the desired compound (3.13 g, yield: 80.2% ) , m.p. 80°-81° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2>>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:16]/[C:13]1[NH:12][C:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=3[C:14]=1[CH3:15])/[C:31](=[O:37])[NH:32]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 25.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 were used as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 42 (25 mg, yield 25.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccc(I)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Product: O=C(c1ccc(I)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of intermediate (38) (0.0103 mol) in phosphoryl chloride (20 ml) was stirred and refluxed for 1 hour. The mixture was cooled to room temperature and evaporated till dryness. The residue was taken up in DCM. This solution was poured out into ice/NH4OH and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (5.3 g) was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried, yielding 4.25 g (82%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-iodophenyl)-methanone, mp. 153° C. (intermediate 39).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[CH:17](O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[CH:7]=[C:8]2[N:9]=[CH:17]1
Reactant: CNc1ncc(C(F)(F)C(F)(F)F)cc1N
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1cnc2cc(C(F)(F)C(F)(F)F)cnc21

Procedure:
A mixture of 0.42 g of N2-methyl-5-pentafluoroethylpyridine-2,3-diamine, 4 ml of formic acid and 0.5 ml of water was stirred under heating and refluxing for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 7.80 g of 3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:30][C:31]([OH:33])=O)[C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1.[C:34]([O:38][C:39]([NH:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20](=[O:29])/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][C:31]([N:44]2[CH2:45][CH2:46][C@H:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:43]2)=[O:33])=[CH:17][CH:18]=1
Reactant: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (9.39 g, 0.049 mol) was added to a solution of {(4-Bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid 2 (13.82 g, 0.038 mol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (9.13 g, 0.049 mol), 1-hydroxy-7-azabenzotriazole (6.67 g, 0.049 mol) and N-methylmorpholine (8.4 mL, 0.08 mol) in DMF (150 mL). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×3), brine, saturated aqueous sodium bicarbonate (×2) and brine. The title compound began to crystallize during work-up and was collected by filtration. The mother liquor was concentrated to provide a further quantity of product. Total yield of title compound: 17.43 g, 86%. 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.60 (3H, s), 1.7-2.3 (2H, m), 3.4-3.8 (4H, m), 4.1-4.9 (3H, m), 6.36 (1H, d, J=16 Hz), 7.36 (2H, d), 7.2-7.4 (5H, m), 7.55 (2H, d) and 7.70 (1H, d, J=16 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)[N:29]=1)=[O:21]
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide to yield a light yellow solid (6.7%). LCMS: m/z=499.46 (M+H+), 1H NMR (400 MHz, CDCl3) δ8.28 (m, 1H), 8.09 (d, 1H, J=1.8 Hz), 7.74 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 3.78 (m, 2H), 2.96 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.36 (m, 6H), 1.21 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.O.[NH2:13][NH2:14]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:13][NH:14]2)=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(Cl)cc1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Fc1cc2cn[nH]c2cc1Cl
Temperature: 140 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 4-chloro-2,5-difluorobenzaldehyde (20.6 g, 105.0 mmol) and hydrazine hydrate (77.2 mL, 1575.2 mmol, 15 eq) in n-butanol (35 mL) was stirred at 140° C. for 3 days. The mixture was cooled to room temperature and poured into ice water (750 mL). The mixture was stirred vigorously for 2 h, and the orange solid was filtered. The filtrate was extracted with EtOAc (3×250 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was combined with the orange solid and then purified by MPLC (Biotage®, gradient elution 25% EtOAc/hexane) to give 2.81 g (16%) of a white solid. 1H-NMR (300 MHz, DMSO-d6) 13.3 (broad s, 1H), 8.09 (s, 1H), 7.80 to 7.76 (m, 2H); ES-MS m/z 171.2/173.2 [M+H]+, RT (min) 3.02.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].COC1C(OC)=NS(=O)(=O)N=1.CO[C:24]1[C:28]([NH:29][CH2:30]CSCC2SC=CN=2)=[N:27][S:26](=[O:40])(=[O:39])[N:25]=1.CN>>[CH3:30][NH:29][C:28]1[C:24]([NH:10][CH2:9][CH2:8][S:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[N:25][S:26](=[O:40])(=[O:39])[N:27]=1
Reactant: NCCSCc1nccs1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nccs1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nccs1

Procedure:
When a methanolic solution of 2-[(thiazol-2-yl)methylthio]ethylamine [prepared according to the procedure described in U.S. Pat. No. 3,950,333] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and the resultant 3-methoxy-4-{2-[(thiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide treated with methylamine according to the general procedure described in Example 31, the title compound is thereby produced.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I147) (0.061 g, 0.10 mmol) in DMF (9 mL) and triethylamine (1 mL) was added a slurry of Pd/C (0.070 g) in DMF (3 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 16 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was taken up in DMF (9 mL) and triethylamine (1 mL). A slurry of Pd/C (0.070 g) in DMF (3 mL) was added and the resulting mixture was stirred under an atmosphere of hydrogen at room temperature for a further 19 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was chromatographed (Biotage Isolera: 25 g silica cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I148) (0.030 g, 49%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.61-7.46 (m, 4H, NH), 7.19 (d, J=8.6 Hz, 2H), 7.12 (dd, J=7.7, 4.8 Hz, 1H), 4.35-3.99 (m), 3.72 (s, 2H), 3.70 (s, 3H), 3.37 (J=7.4 Hz, 2H), 3.28 (t, J=6.9 Hz, 2H), 2.80-2.57 (m, 3H), 2.07-1.95 (m), 1.91-1.69 (m, 2H), 1.69-1.50 (m, 3H), 1.46 (s, 9H). LCMS Method C: rt=6.00 min, m/z 600.2 [M+H]+.