Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([NH:17][C:18](=[O:35])[CH:19]([NH:24][S:25]([C:28]3[C:29]([CH3:34])=[N:30][O:31][C:32]=3[CH3:33])(=[O:27])=[O:26])[CH2:20]C(C)C)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([NH:17][C:18](=[O:35])[CH:19]([NH:24][S:25]([C:28]3[C:29]([CH3:34])=[N:30][O:31][C:32]=3[CH3:33])(=[O:27])=[O:26])[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)NC(CC(C)C)C(=O)NC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1noc(C)c1S(=O)(=O)NC(C)C(=O)NC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O

Procedure:
The compound of Example 65 was synthesized using a procedure analogous to the synthesis of the compound of Example 59 but using N-Boc-(L)-alanine in the second step. MS (ESI) M+H=530.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:13][C:14](O)=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[C:5]1([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:13][C:14]([Cl:3])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)COC(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)COC(c1ccccc1)c1ccccc1
Yield: 72.7 %

Procedure:
8.1 g (68.1 mmole) of thionyl chloride was added to a solution of 5.5 g (22.7 mmole) of (diphenylmethoxy) acetic acid in 150 cm3 of benzene. The solution was refluxed for 5 hours, then evaporated to dryness under reduced pressure. Distillation of the residue yielded 4.3 g (yield: 73%) of (diphenylmethoxy) acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15](Cl)[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: OCCCCl
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccccc1N1CCN(CCCO)CC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
46 g of 1-(2-methoxyphenyl)-piperazine and 24.5 g of trimethylene chlorohydrine are dissolved in 200 ml of ethanol, and 25 g of potassium carbonate are added to the solution. The mixture is refluxed for 30 hours, thereafter it is cooled to 0° C., diluted with 50 ml of ethyl ether, filtered, and the filtrate is evaporated. The residue is dissolved in 100 ml of 50° C. benzene, the solution is cooled to 0° C., and allowed to stand for 10 hours. The separated crystals are filtered off and dried. 46 g (77%) of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-hydroxy-propane are obtained; m.p.: 92°-93° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br-:26].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:26])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Br-]
Reactant: CC(=O)N1CCc2ccc(N3CCN(C)CC3)cc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(Br)c(N3CCN(C)CC3)cc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A stirred mixture of 1-acetyl-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1H-indole (D11, 2.0 g, 0.0077 mole) and anhydrous potassium carbonate (2.12 g, 0.015 mole) in a mixture of dichloromethane (100 ml) and methanol (50 ml) at -5° C. under argon was treated portionwise over 20 minutes with benzyltrimethylammonium tribromide (3.14 g, 0.0081 mole). The mixture was allowed to warm to room temperature over 1 h, then concentrated in vacuo and the residue dissolved in dichloromethane (150 ml), washed with water (2×100 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (2.52 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][O:10][C:11](=[O:33])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][C:21]([C:29]#N)=[CH:22][N:23]2CCOCC2)=[CH:14][C:13]=1[O:31][CH3:32]>C(O)(C)C>[CH3:9][O:10][C:11](=[O:33])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH2:20][C:21]([C:22]#[N:23])=[CH:29][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[O:31][CH3:32]
Reactant: COC(=O)c1c(OC)cc(CC(C#N)=CN2CCOCC2)cc1OC
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC
Reaction time: 0.5 h

Procedure:
8.6 G. of aniline were treated under cooling with 7.6 ml. of concentrated hydrochloric acid. Subsequently, 32 g. of 4-(2-cyano-3-morpholinoallyl)-2,6-dimethoxybenzoic acid methyl ester and 100 ml. of isopropanol were added. The suspension was heated at reflux with stirring for 30 minutes. About 1/3 to half of the solvent was evaporated and 20 ml. of water added. The resulting crystalline product was removed by filtration under vacuum, washed with a little cold methanol and dried. Recrystallization from methanol yielded 4-(3-anilino-2-cyanoallyl)-2,6-dimethoxybenzoic acid methyl ester of m.p. 193°-194°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]2[C:8](=[O:20])[C:9]3[NH:10][CH:11]=[N:12][C:13]=3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]2=[N:5][N:4]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:20])[N:7]3[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]=2[N:12]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(SC)nnc12

Procedure:
A solution of 3-(methylthio)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (111 mg, 0.380 mmol), N-bromosuccinimide (81.1 mg, 0.456 mmol) in THF (3 ml) was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H16BrN6OS (M+H) 371.0. found: 371.0, 373.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O)[CH3:37]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:29]=[C:30]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[CH2:38][N:36]([CH3:37])[CH3:35])[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: CN(C)Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5CN(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(N,N-dimethylaminomethyl)-phenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.Cl.[NH2:30][OH:31]>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[N:30][OH:31])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: COC1(c2cc(OCc3ccc4c(c3)OCCC4=O)nc(N)n2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(OCc3ccc4c(c3)OCCC4=NO)nc(N)n2)CCOCC1
Yield: 79 %

Procedure:
Using an analogous procedure to that described in Example 43, 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yloxymethyl]chroman-4-one was reacted with hydroxylamine hydrochloride to give 7-[2-amino-6-(4-methoxytetrahydropyran-4-yl)pyrimidin-4-yl-oxymethyl]chroman-4-one oxime in 79% yield, m.p. 224°-228° C.;
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].O.Br[CH2:12][C:13]([CH2:15][C:16]([NH:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]12)=[O:17])=O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:12]=[C:13]([CH2:15][C:16]([NH:18][CH:19]2[C:39](=[O:40])[N:21]3[C:22]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]23)=[O:17])[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Thiourea (1.13 g), sodium bicarbonate (1.24 g) and water (20 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g) in tetrahydrofuran (60 ml), and stirred at room temperature for an hour. After concentrating the resultant solution under reduced pressure, the residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[F:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[CH:15]1([C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([F:28])[C:30]([OH:45])=[C:31]([F:44])[CH:32]=2)=[C:11]([F:12])[CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(-c4cc(F)c(O)c(F)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]-7-fluoroquinolin-3-yl}(cyclopropyl)methanone (43 mg, 0.099 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.149 mmol) to afford the desired product (14 mg, 29%) as a light yellow solid: NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 7.68 (d, J=11.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 2H), 4.31 (s, 1H), 3.47-3.35 (m, 1H), 3.27 (s, J=6.8 Hz, 1H), 2.88 (s, 5H), 2.87-2.75 (m, 1H), 2.43 (s, 2H), 2.26 (s, 2H), 1.88-1.64 (m, 4H), 1.35-1.13 (m, 4H), ESI MS m/z 484 [C27H28F3N3O2+H]+; HPLC 98.3% (AUC), tR=8.83 min.
Reaction SMILES: N1CCCC1.[N:6]1([CH2:12][C:13](=[CH2:17])[C:14](=[O:16])[CH3:15])[CH2:11][CH2:10]C[CH2:8][CH2:7]1.N1(CC(CN2CCCCC2)C(C)=O)CCCCC1>>[CH2:7]([N:6]([CH2:12][C:13](=[CH2:17])[C:14](=[O:16])[CH3:15])[CH2:11][CH3:10])[CH3:8]
Reactant: C=C(CN1CCCCC1)C(C)=O
Agent: CC(=O)C(CN1CCCCC1)CN1CCCCC1
Solvent: C1CCNC1
Product: C=C(CN(CC)CC)C(C)=O

Procedure:
The intermediate olefinic ketone is prepared by the procedure of H. M. E. Carwell [J. Chem. Soc., 1058 (1950)]. The ketone obtained from A., 22.8 g., in 25 ml. of ethanol was added to a solution of 25 g. of anhydrous oxalic acid in 75 ml. of ethanol. The mixture was cooled to 0° C., filtered to remove diethylamine hydrogen oxalate and the mother liquor evaporated to dryness under reduced pressure. The residue was dissolved in a little water, treated with potassium carbonate and extracted with ether. The ether was dried over anhydrous sodium sulphate and the residue obtained by solvent removal was distilled. After re-distillation the product was obtained as an oil, b.p. 82° C./18 mm. Similarly, the other 1,1-bis-(disubstituted aminomethyl)acetones obtained as in A. can be converted to the corresponding 3-disubstituted aminomethylbut-3-en-2-ones. The disubstituted amino term as previously indicated also comprises pyrrolidine and piperidine alicyclic ring analogs. For example, 3-(piperidinomethyl)but-3-en-2-one boils at 135°-139° C./15 mm. and is synthesized following the same procedure from 1,1-bis(-piperidinomethyl)acetone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(OC(O)C)C>[CH:18]([NH:21][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cncc(-n2cnc3ccc(N)cc32)n1

Procedure:
A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and isopropylamine (350 μL, 4.1 mmol) in ethoxyethanol (2 mL) containing DIPEA (140 μL) was heated in a sealed tube overnight under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H2O (20 mL) and brine (20 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with dichloromethane-methanol (9:1-94:6) to separate pure product from the lower fractions (102 mg).
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.[CH2:24]([Al](CC(C)C)CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:24]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.2 g., 0.645 mmole) in toluene (4 ml.) was added dropwise over 10 minutes to a solution of triisobutylaluminum (0.91 M in hexane, 0.9 ml., 0.816 mmole) in toluene (2 ml.) at -40° C. The mixture was stirred at -50° C. for 4 hours and at -40° C. for one hour. A solution of triisobutylaluminum (1 ml., 0.91 mmole) was added to the reaction mixture. After stirring for 30 minutes the reaction was quenched by adding 10% hydrochloric acid (2 ml.) at -40° C. The organic phase was washed with brine, dried (magnesium sulfate), and the solvent was evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (30% ethyl acetate/hexane) Rf =0.3. The product contained about 5% of the isomeric compound; TLC (30% ethyl acetate/hexane) Rf =0.2.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:15][C:16](OCC)=O)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)([O-])=O.CC[OH:23]>[Ni]>[O:12]1[C:8]2([CH2:13][CH2:14][C:5]3([CH2:15][CH2:16][NH:1][C:4]3=[O:23])[CH2:6][CH2:7]2)[O:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Reactant: CCO
Agent: [Ni]
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
To a solution of ethyl 2-(8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-yl)acetate (109 g, 379.38 mmol) in EtOH (600 mL) was added Raney Ni (10 g). The reaction mixture was stirred at rt under H2 atmosphere for 72 h and filtered. The filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filtrated was concentrated in vacuo and the residue was washed with a mixture of PE and EtOAc (10/1 (v/v), 800 mL) and filtered to give the product as a white solid (67 g, 83.8%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:28])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:28][C:9](=[O:11])[CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=23)=[CH:15][CH:14]=1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: O=C(Cc1cccnc1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1

Procedure:
3-Pyridylacetic acid hydrochloride and the product from Example 99A were processed using method analogous to that described in Example 98 to afford the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 8.85 (dd, J=7.0, 1.8 Hz, 1H), 8.55 (dd, J=4.1, 1.8 Hz, 1H), 8.52-8.55 (m, 1H), 8.46-8.50 (m, 1H), 7.78-7.89 (m, 1H), 7.60-7.64 (m, 2H), 7.37-7.45 (m, 1H), 7.29-7.32 (m, 2H), 7.06 (dd, J=7.0, 4.1 Hz, 1H), 3.81 (s, 2H); MS (ESI) m/z 364 (M+H)+; Anal. calculated for C19H14ClN5O.0.35H2O: C, 61.66; H, 4.00; N, 18.92. Found C, 61.40; H, 3.70; N, 18.77.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a THF (200 mL) solution containing 3-(4-fluorophenyl)propanoic acid (33.6 g, 0.2 mol) was added a 1.0 M solution of LiAlH4 in Et2O (200 mL, 0.2 mol) over a period of 0.5 h. The resulting mixture was allowed to stir at RT for 18 h. The reaction was slowly quenched with H2O and the aqueous layer extracted (1×) with Et2O. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The resulting oil was used in the next step without further purification. Isolated 31.4 g (0.2 mol, 100% yield).
Reaction SMILES: COC([N:5]1[C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C@@H:9]([NH:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[CH2:8][CH2:7][CH2:6]1)=O.[OH-].[Na+]>C(O)C>[CH3:16][C:14]1[CH:13]=[C:12]([CH3:17])[C:11]2[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:18][C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)[C:10]=2[CH:15]=1
Reactant: COC(=O)N1CCC[C@H](Nc2nnn(C)n2)c2cc(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2c(c1)[C@@H](Nc1nnn(C)n1)CCCN2
Temperature: 85 °C
Yield: 84.4 %

Procedure:
Combine methyl-(5S)-7,9-dimethyl-5-[(2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (20.1 g), NaOH (12.10 g), and ethanol (80 mL) in a 250 mL teflon flask with overhead stirring. Sparge with nitrogen for 10 minutes, heat to reflux (85° C.) for ˜5.5 hours. Cool to room temperature with a cool water bath. Add acetic acid/water (17.5 mL/53 mL) slowly at room temperature and transfer to 500 mL flask about half way through addition (˜30 min total time for addition). Seed with ˜5 mg of (5S)-7,9-dimethyl-N-(2-methyltetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine Heat to 50° C. (up to temperature in about 15 minutes). Add 54 mL of water over about 30 minutes. The next day, cool in ice bath, filter and rinse with methanol:water (1:1; 2×30 mL). Dry wet cake in vacuo at 60° C. to yield 13.99 g of (5S)-7,9-dimethyl-N-(2-methyltetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine HPLC analysis: 99.4%, ret time is 4.84 min. Chiral HPLC: 98.5% chiral purity.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:27])[C:12]([CH3:26])([CH3:25])[O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[Ce+3].[Cl-].[Cl-]>O>[CH3:26][C:12]1([CH3:25])[C:11](=[O:27])[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[O:13]1
Reactant: CC(=O)c1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: CC(O)c1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
A mixture of 4-(4-acetylphenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (150 mg, Example 10), sodium borohydride(35mg) and cerium(III) chloride (20 mg) in 40 ml methaol was stirred at room temperature for 12 hours, which was followed by addition of water. Then the methanol was removed in vacuo and the resulting aqueous solution was extracted with ethylacetate. The ethylacetate layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to obtain 100 mg of 2,2-dimethyl-4-{4-(1-hydroxyethyl)phenyl}-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ1.51-1.53 (d, J=6.3 Hz, 3H), 1.58 (s, 6H), 3.07 (s, 3H), 4.90-4.97 (q, J=6.3 Hz, 1H), 7.25-7.28 (m, 2H), 7.39-7.42 (m, 2H), 7.84-7.86 (m, 2H), 7.92-7.95 (m, 2H). IR (cm−1): 3502, 2977, 1696, 1594, 1317, 1149 960, 771.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:33])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCO3)ncc1Cl

Procedure:
Into an 8 ml sealed tube was placed 2-Amino-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one (0.080 g, 0.45 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.16 g, 0.49 mmol), and 10-Camphorsulfonic acid (0.11 g, 0.49 mmol). Isopropyl alcohol (2 mL, 0.03 mol) was added. The reaction was microwaved at 120° C. for 40 minutes, diluted with CH2Cl2, washed with aqueous sat'd NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by silica gel chromatography (ISCO amine column 0-100% EtOAc in hexanes) to afford title compound as a yellow solid. LCMS: 457.17 (M+H), HPLC: 95% purity, 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.80 (s, 1H), 7.45-7.40 (m, 3H), 7.35-7.31 (m, 2H), 6.90 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.43 (bd, 4.0 Hz, 1H), 4.42 (t, J=5.8 Hz, 2H), 2.94 (d, J=4.8 Hz, 3H), 2.81 (t, J=5.6 Hz, 2H).