Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C@H:9]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[NH2:7][C@@:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[C@H:9]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC1CN(C(=O)C(F)(F)F)[C@H]2c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@]12CC1CN(C(=O)C(F)(F)F)[C@H]2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing the racemic Intermediate 53, one enatiomer being [(1S,2S)-2-phenyl-3-(2,2,2-trifluoro-acetyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (4.3 g, 11.5 mmol) and methylene chloride (75 mL) was immersed in a 0° C. bath, trifluoroacetic acid (8.0 mL, 103 mmol) was added dropwise, and the reaction stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stir for 5 hours. The solvent was removed at reduced pressure and the material dried in vacuo to give the title compound as a trifluoroacetic acid salt. (quantitative yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].CO.[BH4-].[Na+]>O>[CH3:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[OH:11]
Reactant: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1ccc(C(C)O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 89 %

Procedure:
(a-2) To a stirred mixture of 19.4 parts of 1-[4-(methylamino)-3-nitrophenyl]ethanone and 160 parts of methanol were added dropwise 4 parts of sodium tetrahydroborate. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was poured into 1000 parts of water and the product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 17 parts (89%) of α-methyl-4-(methylamino)-3-nitrobenzenemethanol as a residue (int. 88).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:30][C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)=[N:31][C:7]=3[C:6]=2[CH:18]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2cc(Br)ccc2NC(=O)C3)cc1
Yield: 99 %

Procedure:
Analogous to Scheme 1, from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 99%. White solid, m/z (ISP) 410/412 (MH).
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH:4](C(=O)C)[CH2:5][CH2:6][CH2:7]2.[C:14](C1C2NC(CCC=1)CC2)(=[O:16])C.C[N:27]1C2CCC1C(C(=O)C)CC2>>[CH3:14][O:16][N:27]=[C:7]1[CH2:6][CH2:5][CH2:4][CH:10]2[CH2:9][CH:8]1[N:2]([CH3:1])[CH2:3]2
Reactant: CC(=O)C1CCC2CCC1N2C
Reactant: CC(=O)C1=CCCC2CCC1N2
Reactant: CC(=O)C1CCCC2CCC1N2C
Product: CON=C1CCCC2CC1N(C)C2

Procedure:
Similarly when N-methyl-2-acetyl-9-azabicyclo [4.2.1]nonane, which can be prepared from 2-acetyl-9-azabicyclo [4.2.1]non-2-ene which is commercially available, is substituted for N-methyl-2-acetyl-8-azabicyclo [3.2.1]octane, compound (5) , N-methyl-8-azabicyclo [4.2.1 ]nonan-2-one methyl oxime is obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[S:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[C:8]=2[C:20](OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:34]1(=O)[CH2:39][CH2:38]C[CH2:36][CH2:35]1.P(=O)(O)(O)O.C([SiH](CC)CC)C>C(O)(=O)C>[CH:20]1([C:8]2[C:9]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:38][CH2:39][CH2:34][CH2:35][CH2:36]1
Reactant: CCOC(=O)c1cc2c(C(=O)OC(C)(C)C)c(-c3ccccc3)[nH]c2s1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution (0.2 M) of 4-tert-butyl 2-ethyl 5-phenyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. overnight, then it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was dissolved in TFA and cooled to 0° C. The resulting solution (0.1 M) was treated with triethylsilane (2 eq.) and stirred at 0° C. for 1 h then solvent was evaporated to give a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (58%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][NH:36][S:33]([C:29]1[CH:28]=[CH:27][CH:32]=[C:31]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:30]=1)(=[O:34])=[O:35]
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-methyl-benzenesulfonamide (example B.32) (225 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 68%). MS (ISP) 525.2 [(M+H)+]; mp 213–214° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH:21]=[O:22])[C:19]=1[CH3:20])[CH2:5][N:6]([CH:14]1[CH2:16][CH2:15]1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:23][C:24]1[CH:25]=[C:26]([Mg]Br)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[C:9]([O:8][C:7](=[O:13])[N:6]([CH2:5][C:4]1[CH:17]=[C:18]([CH:21]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)[OH:22])[C:19]([CH3:20])=[C:2]([Br:1])[CH:3]=1)[CH:14]1[CH2:15][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C=O
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1c(Br)cc(CN(C(=O)OC(C)(C)C)C2CC2)cc1C(O)c1cccc(F)c1
Temperature: 25 °C

Procedure:
To a THF (0.13 M) solution of tert-butyl (3-bromo-5-formyl-4-methylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step was added at 0° C. 3-fluorophenyl magnesium bromide (0.5 M in THF, 1.1 eq.). The resulting solution was warmed slowly to RT over 2 h before it was quenched with sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](C(OC)=O)([C:18]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[Cl-].[Na+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCC(C(=O)OC)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCC(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Product: COC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: 21 °C
Yield: 45 %
Yield: 38 %

Procedure:
A solution of compound Trimethyl 1-(2-fluoro-4-nitrophenyl)propane-1,1,3-tricarboxylate (85) (0.23 g, 0.63 mmol), sodium chloride (0.11 g, 1.90 mmol) and water (0.15 mL) in distilled dimethylsulfoxide (4 mL) was heated to 155° C. overnight. The reaction mixture was allowed to cool to 21° C. and then worked up by adding water and extracting with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 8:1) to give desired Methyl 4-(2-fluoro-4-nitrophenyl)butanoate (84) (69 mg, 45%) and dimethyl 2-(2-fluoro-4-nitrophenyl)pentanedioate (83) (72 mg, 38%): 1H NMR of (10) δ 8.04 (dd, 1H, J=8.5, 2.2 Hz), 7.95 (dd, 1H, J=9.5, 2.2 Hz), 7.53 (dd, 1H, J=8.5, 7.1 Hz), 4.08 (t, 1H, J=7.6 Hz) 3.71 (s, 3H), 3.66 (s, 3H), 2.43-2.52 (m, 1H), 2.31-2.35 (m, 2H), 2.06-2.14 (m, 1H); 1H NMR of (84) δ 7.98 (dd, 1H, J=8.4, 2.2 Hz), 7.90 (dd, 1H, J=9.5, 2.2 Hz), 7.38 (dd, 1H, J=8.4, 7.3 Hz), 3.68 (s, 3H), 2.79 (t, 2H, J=7.7 Hz) 2.38 (t, 2H, J=7.3 Hz) 1.94-2.02 (m, 2H).
Reaction SMILES: Cl.[C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:6]1)([OH:4])=[O:3].S(Cl)([Cl:32])=O.[CH2:34](O)[CH3:35]>>[ClH:32].[CH2:34]([O:3][C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:7][CH2:6]1)=[O:4])[CH3:35]
Reactant: O=C(O)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1
Reactant: CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCOC(=O)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3 g of 2-[4-(4-carboxypiperidino)butoxy]bibenzyl hydrochloride in 30 ml of ethanol was added dropwise 0.9 g of thionyl chloride. The reaction mixture was stirred for one hour, heated under reflux for 30 minutes, concentrated in vacuo and then recrystallized from ethanolether to give 2.8 g (87% yield) of 2-[4-(4-ethoxycarbonylpiperidino)butoxy]bibenzyl hydrochloride, m. p. 84°-87° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]1[O:38][CH:37]([CH3:39])[CH2:36][NH:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:39][CH:37]1[O:38][CH:33]([CH3:32])[CH2:34][N:35]([CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[CH:26]=[CH:25][CH:24]=2)[CH2:36]1
Reactant: CC1CNCC(C)O1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CC(C)OC(C)C5)c4)cc23)CC1
Yield: 32.5 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2,6-dimethylmorpholine (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (19.6 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 11.1 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (222 mg, 0.52 mmol) and 2-amino-2-methyl-1-propanol (0.25 mL, 2.62 mmol) were reacted to give the crude material. Purification by Flash chromatography eluting with dichloromethane/ethanol/triethylamine (100/1/2, v/v/v), followed by preparative HPLC, eluting with acetonitrile/H2O (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product 25 mg (11%). LC-MS: 433.4 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](O)[CH:27]=2)=[CH:21][CH:20]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[CH:31]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Oc1cccc(Nc2ccccc2)c1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(Nc3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 3-hydroxydiphenylamine and cleavage from the resin (Standard Procedure G) gave an oily solid (4%). 1H-NMR (200.15 MHz, CDCl3): δ 7.31–6.81 (m, 8H), 6.83 (d, 2H, J=8.6), 6.65–6.62 (m, 2H), 6.48 (dd, 1H, J=8.2, 2.1), 4.12 (t, 4H, J=6.2), 3.99 (dd, 1H, J=7.0, 4.4), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.4), 2.95 (dd, 1H, J=14.2, 7.0), 2.22 (qn, 2H, J=6.2).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Br:18])[CH:13]=O.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[Br:18]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: O=C1COCC(=O)C1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(Br)c(Br)c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
The product from Example 11B (0.17 g, 1.5 mmol), the product from 3,4-dibromobenzaldehyde (0.53 g, 2.0 mmol) and methyl 3-aminocrotonate (0.15 g, 1.3 mmol) in ethanol (8 mL) were heated at 80° C. in a sealed tube for 60 hours and then cooled to ambient temperature. The mixture was filtered and the filter cake was washed with ethanol and dried to provide the title compound (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[C:13]([Br:18])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:14]=[C:13]([Br:18])[CH:12]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: Brc1cc(Br)cc(Br)c1
Product: N#Cc1ccc(Nc2cc(Br)cc(Br)c2)cn1

Procedure:
5-Amino-pyridine-2-carbonitrile was coupled with 1,3,5-tribromobenzene to give 5-(3,5-dibromo-phenylamino)-pyridine-2-carbonitrile by the method described in Example 44. 5-(3,5-Dibromo-phenylamino)-pyridine-2-carbonitrile was converted to [3-bromo-5-(6-cyano-pyridin-3-ylamino)-phenyl]-carbamic acid methyl ester using the conditions in Example 86, replacing methylsulfonamide with carbamic acid methyl ester. [3-Bromo-5-(6-cyano-pyridin-3-ylamino)-phenyl]-carbamic acid methyl ester was converted to [3-(6-cyano-pyridin-3-ylamino)-5-(1H-indol-4-yl)-phenyl]-carbamic acid methyl ester as described in Example 102. 1H NMR (400 MHz, acetone-d6): δ 10.41 (s, 1H), 8.84 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.44 (s, 1H), 7.72-7.63 (m, 4H), 7.46 (d, J=7.6 Hz, 1H), 7.42 (t, J=2.7 Hz, 1H), 7.26 (s, 1H), 7.23-7.14 (m, 2H), 6.75 (s, 1H), 3.73 (s, 3H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].Br[CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-:17].[Cs+].[Cs+]>C(#N)C>[O:17]1[C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: BrCCCBr
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCCCO2
Temperature: 60 °C

Procedure:
A mixture of 35 g of 3,5-dihydroxybenzaldehyde, 50 g (0.97 equiv) of 1,3-dibromopropane and 127 g (1.5 equiv) of cesium carbonate in 1 L of anhydrous acetonitrile was heated under nitrogen to 60° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 500 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-20% ethyl acetate in hexanes) gave the product as clear oil. MS (m+1)=179.1; 1H NMR (400 MHz, CDCl3) 9.82 (s, 1H), 7.42 (m, 2H), 7.02 (m, 1H), 4.32 (t, 2H), 4.24 (t, 2H), 2.22 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=2[O:31]1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])[C:32]=2[O:31]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cccc3c2OC(C)(C)C3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-ol (0.25 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.C(I)[I:19].[N+]([O-])(OCCC(C)C)=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:19])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ccc(C)cn2)c1
Reactant: ICI
Agent: CC(C)CCO[N+](=O)[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamyl nitrate using the procedure of step 5 of preparation 6, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1([CH3:22])[CH2:17][O:16][CH:15]([CH2:18][CH2:19][CH2:20][OH:21])[O:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:22])[CH2:13][O:14][CH:15]([CH2:18][CH2:19][CH:20]=[O:21])[O:16][CH2:17]1
Reactant: CC1(C)COC(CCCO)OC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(CCC=O)OC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
DMSO (10.2 ml, 0.14 mol) was added to a solution of oxalyl chloride (5.5 ml, 63.2 mmol) in methylene chloride (25 ml) at −78° C. After stirring for 15 min, a solution of 5,5-dimethyl-1,3-dioxane-2-propanol (Step 1) (10 g, 57.5 mmol) in methylene chloride (100 ml) was added over 10 min. The reaction was stirred for 1 hr and triethylamine (40 ml, 0.2 mol) was added. After stirring at −70° C. for 1 hr, the reaction mixture was warmed to room temperature and stirred for 2 hr. The reaction was quenched with water and extracted with methylene chloride. The organic fractions were washed with aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration, the crude compound was chromatographed (silica gel, hexane/ethyl acetate 7/3) to give 5,5-dimethyl-1,3-dioxane-2-propanal (6.1 g, 61%) as a colorless liquid: Anal Calc'd. for C9H16O3 0.2 H2O: C, 61.48; H, 9.40. Found: C, 61.46; H, 9.24.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.CN(C)C=O>CCOCC>[CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCOC(=O)C2CC2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCOC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3.2 g (12.8 mmol) of 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid, 80 ml of ether and 1.5 ml (20.5 mmol) of thionyl chloride, at RT, is added 0.3 ml (3.8 mmol) of dimethylformamide. This mixture is stirred, at RT, for 1 day. The top phase is decanted (the residue is discarded), and solvent and ohter volatiles are removed from it by rotoevaporation to give 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid chloride.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOCCc1ccccn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added 2-[2-(aminooxy)ethyl]pyridine 125 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373). 1-hydroxybenzotriazole (0.14 g, 1.10 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 91%) as a clear thick oil.