Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:31][C:32]([F:39])([F:38])[C:33](OCC)=[O:34].O>CO>[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:33](=[O:34])[C:32]([F:39])([F:38])[F:31])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (−)-(cis)-7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (2.32 g, 6.09 mmol) in a mixture of methanol (80 mL) and triethylamine (5.1 mL, 36.3 mmol), ethyl trifluoroacetate (4.3 mL, 36.3 mmol) was added and the resulting mixture was stirred at ambient temperature for 2 h. Water (120 mL) was added and stirred for additional 10 min. The formed precipitate was filtered off to yield the title compound (2.74 g, 94%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C1(C)C=CC=CC=1>[CH3:15][Si:16]([CH3:19])([CH3:18])[N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
To 400 g (4 moles) of succinimide and 900 ml of triethylamine in 2700 ml of toluene 780 ml of trimethylchlorosilane were added in two hours with vigorous stirring. After refluxing and stirring for an additional hour the mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with 1 l of toluene and 1 l of light petrol (40°-60° C.) and the combined filtrate and washings concentrated to about 700 ml. N-trimethylsilylsuccinimide was isolated by distillation at diminished pressure. The yield was 573 g (3.35 moles) or 83.5%; boiling point 62° C./0.3 mm Hg.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH3:34]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[C:27]([CH3:34])[CH:28]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: Cc1cc(CBr)ccc1F
Product: Cc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)ccc1F
Yield: 0.9 %

Procedure:
The title compound (0.001 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.43 (m, 4H), 7.08-7.06 (m, 1H), 6.99-6.97 (m, 2H), 5.32 (s, 2H), 3.88 (s, 2H), 3.16-3.14 (m, 2H), 2.89-2.86 (m, 2H), 2.22 (d, J=1.6 Hz, 3H), 1.80 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.O.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([O:24][C:25]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C=CC[C@H](N)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of L-2-amino-4-pentenoic acid (2.0 g) in Dioxane (80 mL) at RT was added triethylamine (4.3 g), water (2.0 mL), and N-(benzyloxycarbonyloxy)succinimide (9.1 g). The reaction mixture was stirred overnight at RT, concentrated in vacuo, diluted with saturated NaHCO3 and extracted with ether (3×). The basic aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc (3×). The combined EtOAc layer was washed with brine, dried (Na2SO4), filtered and evaporated, then concentrated from Toluene (2×) to give a viscous oil (4.51 g, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 2.31-2.50 (m, 2H), 4.00-4.06 (m, 1H), 5.03 (s, 2H), 5.05-5.12 (m, 2H), 5.71-5.84 (m, 1H), 7.35 (m, 5H), 7.53 (d, 1H), 12.57 (bs, 1H). MS APCI, m/z=250 (M+1). LC/MS 2.30 min., Method A.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10](C(OC(C)(C)C)=O)[C:7]2=[CH:8][N:9]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([C@H:33]3[CH2:35][C@H:34]3[F:36])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1.ClC1N=C(NC2C=C(C3CC3)NN=2)C=CN=1>>[NH:10]1[C:7]2[C:8](=[N:9][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:32]=[C:31]([C@H:33]5[CH2:35][C@H:34]5[F:36])[NH:30][N:29]=4)[CH:24]=[CH:23][N:22]=3)[CH3:3])=[CH:5][CH:6]=2)[CH:12]=[CH:11]1
Reactant: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Reactant: F[C@@H]1C[C@@H]1c1cc(Nc2ccnc(Cl)n2)n[nH]1
Agent: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Product: C[C@H](Nc1nccc(Nc2cc([C@H]3C[C@H]3F)[nH]n2)n1)c1ccc2[nH]ccc2n1

Procedure:
The title compound was prepared following the procedure according to Example 9, using (S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (referential example 17) and 2-chloro-N-(5-((1R,2R)-2-fluorocyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (referential example 4) in place of (1H-pyrrolo[3,2-b]pyridin-5-yl)methanamine and 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (referential example 1), respectively, as starting materials. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (br s, 1H), 11.18 (s, 1H), 9.33 (br s, 1H), 7.79 (d, J=5.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.93 (br s, 1H), 6.53 (s, 1H), 6.40 (br s, 1H), 6.10 (br s, 1H), 5.21 (s, 1H), 4.90 (d, J=65.8 Hz, 1H), 2.10-1.99 (m, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.33 (s, 1H), 1.24 (s, 1H); MS (ESI) m/k: 379.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](CS(N)(=O)=O)=[N:6][C:7](CS(N)(=O)=O)=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[N:31](C)[C:32](=O)[CH3:33].CO>C(N(CC)CC)C>[NH:23]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([NH:31][C:32]2[CH:33]=[CH:8][CH:9]=[CH:4][CH:5]=2)[N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)N(C)C
Reactant: NS(=O)(=O)Cc1nc(CS(N)(=O)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2)nc1Nc1ccccc1
Temperature: 140 °C
Yield: 70 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dinitro-2,6-pyridine dimethanesulfonamide (50 g, 0.14 mole), 200 ml aniline and 250 ml N,N-dimethylacetamide was heated with stirring to 140°C and then maintained at this temperature for 6 hours. The warm (90°C) mixture was poured onto 450 ml methanol with stirring and 20 ml triethylamine added. The precipitate was washed with methanol and dried to afford 2,6-dianilino-3,5-dinitropyridine (34.5 g, 70%) as an orange solid, mp. 224-225.5. Anal. Calcd. for C17H13N5O4 : C, 58.1; H, 3.7. Found: c, 57.4; H, 3.4.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[O:26][CH2:27][C:28]([F:55])([F:54])[C@:29]([C:35]3[N:40]=[C:39]([NH:41][C:42]([C:44]4[C:49]([CH3:50])=[CH:48][C:47]([C:51]#[N:52])=[CH:46][N:45]=4)=[O:43])[CH:38]=[CH:37][C:36]=3[F:53])([CH2:31][CH2:32][O:33][CH3:34])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[NH2:24][C:25]1[O:26][CH2:27][C:28]([F:54])([F:55])[C@:29]([C:35]2[N:40]=[C:39]([NH:41][C:42]([C:44]3[C:49]([CH3:50])=[CH:48][C:47]([C:51]#[N:52])=[CH:46][N:45]=3)=[O:43])[CH:38]=[CH:37][C:36]=2[F:53])([CH2:31][CH2:32][O:33][CH3:34])[N:30]=1
Reactant: COCC[C@]1(c2nc(NC(=O)c3ncc(C#N)cc3C)ccc2F)N=C(NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)OCC1(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC[C@]1(c2nc(NC(=O)c3ncc(C#N)cc3C)ccc2F)N=C(N)OCC1(F)F
Yield: 85 %

Procedure:
A solution of 5-cyano-3-methyl-pyridine-2-carboxylic acid {6-[(R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]amino}-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-4-yl]-5-fluoro-pyridin-2-yl}-amide (146 mg, 0.194 mmol), TFA (0.989 ml, 12.83 mmol) and triethylsilane (0.093 ml, 0.583 mmol) in dichloromethane (1.9 ml) was stirred at it for 18 hours. The reaction mixture was evaporated and the residue diluted with ethyl acetate, washed with sat. aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and evaporated. 142 mg colourless resin. The product was chromatographed over a preparative silica gel plate (2 mm, 20×20 cm, Merck, dichloromethane/methanol 95:5) to give the title compound as a colourless foam. 74 mg (85% yield).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH3:11][C:12]1([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[O:14][CH2:13]1>CCOCC.CCCCCC>[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH2:11]=[C:12]([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH2:13][OH:14]
Reactant: CCCC(C)CC(C)CC1(C)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCNCC
Product: C=C(CO)CC(C)CC(C)CCC
Reaction time: 0.17 h

Procedure:
An ice-cold solution of diethylamine (3.48 g, 4.9 ml, 47.55 mmol, dried with KBr) in 10 ml of anhydrous ether was prepared. Next, 19.1 ml of a 2.5M solution of n-butyllithium in hexane was added to the diethylamine solution with stirring under a nitrogen atmosphere. After 10 minutes, a solution of 2,4,6-trimethyl-1,2-epoxynonane (6) (3.50 g, 19.0 mmol) in 10 ml of anhydrous ether was added to the reaction mixture and this mixture was refluxed for one hour. Progress of the reaction was checked by withdrawing samples, quenching with water, and analyzing by TLC. Reaction time was determined to ensure total consumption of the epoxide. Upon completion, the reaction mixture was cooled and poured into ice water. The organic layer was separated and the aqueous layer was saturated with solid sodium chloride and extracted with ether. The combined organic layers were washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution, water, and brine. the solution was dried over sodium sulfate and solvent was removed in vacuo. Vacuum distillation at 85° -90° C. yielded 2-methylene-4,6-dimethylnonan-1-ol (7).
Reaction SMILES: C([CH2:3][C:4](Br)([CH3:8])[C:5]([OH:7])=[O:6])C.C(=O)(O)[O-].[Na+].[Br:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:24].[C:25](OCC)(=O)[CH3:26]>>[Br:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:4]([CH3:3])([CH3:8])[C:5]([O:7][CH2:25][CH3:26])=[O:6])=[CH:18][C:17]=1[CH3:24]
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: CCOC(C)=O
Reactant: CCCC(C)(Br)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Nc1cc(C)c(Br)c(C)c1
Yield: 29 %

Procedure:
Ethyl-2-bromoisobutyric acid (3.7 ml, 24.99 mmol) and sodium bicarbonate (630 mg, 7.49 mmol) were added to 4-bromo-3,5-dimethyl-aniline (500 mg, 2.49 mmol), and the mixture was irradiated with microwaves at 130° C. for 15 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 2-[(4-bromo-3,5-dimethyl-phenyl)amino]-2-methyl-propanoate (230 mg, 29%).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:19][CH2:18]1.[Br:32]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:32])[C:26]=2[F:31])[CH2:19][CH2:18]1
Reactant: CN1CCC(NCc2ccccc2F)CC1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Br)c2F)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Add n-butyl lithium (1.6 M in hexanes, 4.3 mL) into a solution of 2,2,6,6-tetramethyl-piperidine (0.97 g) in THF (10 mL) at −78° C. and stir for 30 minutes. Add a solution of 1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23, 1.02 g) in THF (10 mL) portionwise and stir for 10 minutes. Add 1,2-dibromo-1,1,2,2-tetrachloroethane (1.50 g) in THF (10 mL) dropwise and stir for 1 hr. Remove the cooling bath and stir for 30 minutes. Partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.49 g of the title intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][Mg+].[Br-]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH3:17]
Reactant: C[Mg+]
Reactant: COc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: [Br-]
Product: COc1cc2c(cc1Br)C(C)=CCC2(C)C
Yield: 94 %

Procedure:
Following General Procedure A 7-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 92, 1.0 g, 3.5 mmol) was reacted with MeMgBr to give 0.93 g (94%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:9])[C:7]#[N:8])[C:3]#[N:4].[NH3:10]>>[NH2:4][C:3]1[C:2]([CH3:1])=[CH:5][C:6]([CH3:9])=[C:7]([NH2:10])[N:8]=1
Reactant: CC(C#N)CC(C)C#N
Reactant: N
Product: Cc1cc(C)c(N)nc1N
Temperature: 200 °C

Procedure:
3,5-dimethylglutarimidine is prepared from 2,4-dimethylglutaronitrile using the procedure of Example 2. One equivalent of 3,5-dimethyiglutarimidine is combined with Pd·C catalyst in a Hastelloy shaker tube to which liquid NH3 (59 eq.) is added. The mixture is heated at 200° C. for 45 h. The mixture is cooled to ambient temperature and the excess NH3 removed by N2 purge. The crude mixture is suspended in anhydrous MeOH, the catalyst is removed by syringe filtration, and the crude reaction mixture is concentrated in vacuo. 3,5-dimethylglutarimidine conversion is >90% to give 2,6-diamino-3,5-dimethylpyridine in at least 1% net yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([NH2:19])=[O:18].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:15]2[C:16]=1[C:17](=[O:18])[NH:19][C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1)=[N:14]2
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(NS(C)(=O)=O)cc3)nc2c1
Temperature: 155 °C
Yield: 113.5 %

Procedure:
A mixture of N-(4-formylphenyl)methanesulfonamide (0.161 g, 0.0800 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.0800 mmol), NaHSO3 (94%, 0.00460 g, 0.0240 mmol), and p-TsOH.H2O (0.0125 g, 0.120 mmol) in DMA (1.00 mL) was heated at 155° C. for 16 hours. The mixture was diluted with EtOAc (50 mL), washed with water (2×50 mL), then brine (50 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/MeOH) and the product was freeze-dried from MeCN/H2O to provide the title compound (0.0341 g, 11%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.94 (s, 1H), 10.21 (s, 1H), 8.16 (d, J=8.76 Hz, 2H), 7.30 (d, J=8.76 Hz, 2H), 6.72 (d, J=2.25 Hz, 1H), 6.52 (d, J=2.25 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.09 (s, 3H). MS (ESI) m/z 376 [C17H17N3O5S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:12](Cl)(Cl)=[O:13]>C(O)(=O)C.ClC1C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH2:7][CH2:8][CH2:9][N:10]3[C:12]1=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2c1NCCC2
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: O=c1[nH]c2cccc3c2n1CCC3
Yield: 88 %

Procedure:
To a solution of 10.77 g of 8-amino- 1,2,3,4-tetrahydroquinoline in glacial acetic acid (30 ml) was added dropwise a 21.75% solution of phosgene in chlorobenzene (30 ml), under nitrogen, with stirring. After the addition was complete, the mixture was heated under reflux, with stirring for one hr and evaporated. The residue was taken up in 10% ammonium hydroxide solution (75 ml) and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Ether was added to the residue and the mixture was chilled. The precipitate was collected to give 11.2 g (88%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:50]=[C:49]3[N:45]([CH2:46][CH2:47][C:48]3=[O:51])[CH:44]=2)O1>O1CCOCC1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[CH:50]=[C:49]4[N:45]([CH2:46][CH2:47][C:48]4=[O:51])[CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(c2cc3n(c2)CCC3=O)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3n(c2)CCC3=O)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (10.51 mg, 0.015 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one (148 mg, 0.599 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) was heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(1-oxo-2,3-dihydro-1H-pyrrolizin-6-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (7 mg, 6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.78 (m, 1H), 2.10-2.11 (m, 1H), 3.01-3.04 (m, 2H), 3.34-3.34 (m, 1H), 3.66-3.67 (m, 1H), 3.76-3.78 (m, 1H), 3.84-3.86 (m, 1H), 3.95-3.97 (m, 1H), 4.37-4.39 (m, 4H), 4.50-4.51 (m, 1H), 7.05 (d, J=6.35 Hz, 1H), 7.60 (s, 1H), 7.90-7.92 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H20FN5O3, 386. found, 386.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[CH3:14][C:15](=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:17][CH2:16][C:15](=[O:18])[CH3:14])[C:5]1=[O:13])=[CH2:1]
Reactant: C=CC(C)=O
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(CCC(C)=O)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 34.8 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 28 parts of 3-buten-2-one, 20.2 parts of N,N-diethylethanamine and 270 parts of tetrahydrofuran is stirred and refluxed over week-end. The reaction mixture is evaporated, yielding 48.8 parts (100%) of 1,3-dihydro-1-(1-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cn1
Yield: 59 %

Procedure:
To 250 mg of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 186 mg (59%) of 4-(2,4-dichloro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 75-9° C.; mass spectrum (m/e): M+H 401.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19](O)=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:64][C@@H:65]1[CH2:69][CH2:68][NH:67][C:66]1=[O:70]>C(Cl)Cl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:64][C@@H:65]4[CH2:69][CH2:68][NH:67][C:66]4=[O:70])=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N[C@@H]1CCNC1=O
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 72.6 %

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (850 mg, 1.84 mmol), HATU (837 mg, 2.20 mmol) and DIEA (539 mg, 0.8 mL, 4.6 mmol) in DCM (8 mL) at room temperature for 15 min, followed by addition of (R)-3-aminopyrrolidin-2-one hydrochloride (315 mg, 2.76 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL×3). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (730 mg, 73.0%). MS (m/z): 546 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m, 3H), 6.49 (s, 1H), 5.83 (s, 1H), 4.51-4.48 (m, 1H), 4.22 (d, J=17.2, 1H), 3.85 (d, J=17.2, 1H), 3.52-3.47 (m, 2H), 3.09-2.87 (m, 5H), 2.12-2.03 (m, 1H), 1.89-1.73 (m, 4H).
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CNCc1ccccc1
Reactant: CC[K]
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)N(C)Cc1ccccc1
Yield: 46.4 %

Procedure:
Following the procedure of Example 34, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and N-methylbenzylamine (1.3 g) to give 0.61 g ethyl N-methyl-N-benzyl-2,3-epoxysuccinamate (Compound No. 58) as colorless oil.