Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1([CH:27]=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:18]([O:20][C:21]([C:23]1([CH2:27][NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[N:9]([CH3:17])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Reactant: CCOC(=O)C1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethyl ester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added acetic acid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, the mixture is cooled with an ice-water bath and sodium tri-acetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, the mixture is heated to reflux for 1.5 h, cooled to room temperature, diluted with dichloromethane, washed with 1M aqueous NaOH, water and brine. The combined aqueous phase is extracted once with dichloromethane and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H), 3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8 Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).
Reaction SMILES: I[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:18]#[N:19]>CN1C(=O)CCC1.CCOC(C)=O>[C:18]([C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:19]
Reactant: COC(=O)c1snc(-c2ccccc2)c1I
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1snc(-c2ccccc2)c1C#N
Temperature: 100 °C
Yield: 84.8 %

Procedure:
To a solution of methyl 4-iodo-3-phenylisothiazole-5-carboxylate (Preparation 103D, 600 mg, 1.738 mmol) in NMP (2 mL) was added copper cyanide (311 mg, 3.48 mmol). The resulting mixture was heated at 100° C. in a microwave reactor for 45 min. The reaction mixture was diluted with EtOAc (40 mL), filtered, washed with water (2×20 mL), brine (10 mL) and concentrated. Flash chromatography gave methyl 4-cyano-3-phenylisothiazole-5-carboxylate (360 mg, 1.474 mmol, 85% yield) as a white solid. The compound had an LC/MS M+1=245.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][CH:43]1[CH2:47][O:46][CH:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC(S)CO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3ncccc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4cccc(F)c4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 ml of phosphoryl chloride were added to 0.75 g (1.703 mmol) of the compound from Example 75A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 120 ml of acetonitrile and, with ice cooling, stirred into 72 ml of concentrated ammonia solution (33% in water). The reaction mixture was stirred at room temperature for 3 days and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (acetonitrile/water/water+1% TFA—40:55:5). This gave 134 mg of the title compound (19% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH2:18][CH2:17]1
Reactant: COCCN1CCC(O)CC1
Reactant: O=C1Cc2cc(O)ccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN1CCC(Oc2ccc3c(c2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven dried, nitrogen flushed 100 ml round bottom flask was added 5-hydroxyoxindole (10 mmol), 1-(2-methoxyethyl)-piperidin-4-ol (11 mmol), triphenylphosphine (15 mmol), Anhydrous tetrahydrofuran (35 ml) and a stirrer bar. Diethyl azodicarboxylate (15 mmol) was added slowly to the mixture and stirred at room temperature overnight. The reaction was concentrated in vacuo and flash chromatography (silica, 5% methanol in ethyl acetate). Upon concentration a reddish oil (470 mg) was obtained with a 75% purity by H-NMR and LC/MS.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19]C3(C(O)=O)CCCNC3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:41][O:42][C:43](=[O:50])[CH2:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1>C1COCC1>[CH3:41][O:42][C:43](=[O:50])[CH2:44][CH:45]1[CH2:49][CH2:48][N:47]([CH2:19][CH2:18][CH2:17][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=3)[CH2:46]1
Reactant: O=C(O)C1(CCCN2c3ccccc3CCc3ccccc32)CCCNC1
Reactant: COC(=O)CC1CCNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[CH:25][N:24]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cn1

Procedure:
The title compound was prepared from 4,4,5,5-tetramethyl-2-(4-nitro-phenyl)-[1,3,2]dioxaborolane (899 mg, 3.60 mmol), 5-bromo-2-methoxy-pyridine (616 mg, 3.28 mmol) and Pd(PPh3)4 (380 mg, 0.360 mmol) according to the procedure in Example 44, step (b) (615 mg, 94%). Mass spectrum (ESI, m/z): Calcd. for C12H10N2O3, 231.0 (M+H), found 231.2.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH:6]([CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][C:7](=[O:8])[CH:6]([NH2:1])[CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH3:11]
Reactant: CCOC(=O)C(Br)C(C)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)C(C)C(F)(F)F
Reaction time: 48 h
Yield: 49.7 %

Procedure:
Sodium azide (1.9 g, 28.7 mmol) and ethyl 2-bromo-3-methyl-4,4,4-trifluorobutyrate (5 g, 19.2 mmol) were placed in DMF (20 mL) and stirred for 48 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (4×100 mL). The organic layer was dried over Na2SO4 and solvent was removed. The crude oil was placed in EtOH (20 mL) with 5% Pd/C (1.6 g) and shaken for 6 hours under H2 (50 psi). The reaction was filtered through the Celite® reagent and solvent was removed providing a clear oil (1.9 g) in 50% yield.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([OH:36])(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CC(C)=O.[OH-].[Na+].O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:36][C:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCCCC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 60 ml of acetone is dissolved 1.0 ml of n-octanoic acid, and 3.0 ml of 2N-NaOH, 15 ml of water and 1.8 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are serially added to the above solution. The mixture is refluxed for 4 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of diisopropyl ether, elution is carried out with 300 ml of the same solvent. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.7 g of the above-identified compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:30]4[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1c(F)cccc1F
Reaction time: 20 h
Yield: 41.4 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 2,6-difluorobenzene-sulphonyl chloride (0.62 g) in dichloromethane (22 ml), under nitrogen, and stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave an orange gum. Trituration with petroleum ether (b.p. 40-60° C.) yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzenesulphonamide as an off-white solid (0.29 g); m.p. 122-124° C., [α]D22.5 -22.1° (c=1.0, CH2Cl2).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([C:8](OC)=[O:9])=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:1][CH:2]([F:12])[C:3]1[S:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(C(F)F)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of methyl 5-(difluoromethyl)thiophene-2-carboxylate (2.23 g) in THF (60 ml)-MeOH (15 ml) was added NaBH4 (2.20 g) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.94 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(CCCO)c1cncc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.9 %

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-4-hydroxy-butan-1-one (1) (5.0 g, 20.5 mmole) in 90 mL of CH2Cl2 at 25° C., is added a solution of Dess-Martin periodinane (9.6 g, 22.5 mmole) in 70 mL of CH2Cl2 slowly. After stirring at 25° C. for 20 minutes, the reaction mixture is diluted with 200 mL of ether (a lot of white precipitates came out of the solution) and cooled by dry-ice-acetone bath. The solid is filtered out and discarded. The filtrate is concentrated. The residue is diluted with 100 mL of ether and cooled by dry-ice-acetone bath and precipitates was removed by filtration. The filtrate is concentrated to give 6.2 g of 4-(5-Bromo-pyridin-3-yl)-4-oxo-butyraldehyde (2) as a pale brown oil which turned to a pale brown solid after cooled to 0° C., without further purification for next step reaction.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]4[CH2:22][CH2:21][C:20]5[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=5)[O:14]4)[CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4cc(F)ccc34)CC1)CC2
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.865 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.243 g (62%, 40% ee) of 6-fluoro-3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a tan crystalline powder. [α]D25=−27.14 (c 9.95 in chloroform, 40% ee); Rf=0.47 (silica, ethyl acetate:hexanes 4:1); mp >170° C. dec; Anal. Calcd. for C24H25FN2O2.0.1 H2O: C, 73.11; H, 6.44; N, 7.11. Found: C, 72.81; H, 6.36; N, 7.06.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH2:47])[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1>C1COCC1>[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH:47][C:10](=[O:12])[CH3:11])[C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:34][CH:35]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 27.1 %

Procedure:
Step (b) DIEA (0.10 mL, 0.57 mmol) and acetic anhydride (0.025 mL, 0.27 mmol) was added to (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-amino-N-(4-(4-fluorophenoxy)phenyl)pentanamide (115 mg, 0.269 mmol) in THF (5 mL). The reaction mixture was stirred for 2 hours and then concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 254, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-acetamido-N-(4-(4-fluorophenoxy)phenyl)pentanamide (34 mg, 0.073 mmol, 27%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.21 (s, 1H), 8.75-8.73 (m, 1H), 8.47 (s, 1H), 7.85-7.82 (m, 1H), 7.63-7.58 (m, 2H), 7.24-7.18 (m, 2H), 7.04-6.92 (m, 4H), 4.99 (s, 2H), 4.46-4.38 (m, 1H), 3.12-3.01 (m, 2H), 1.80 (s, 3H), 1.79-1.37 (m, 4H). MS (EI) for C23H25FN6O4. found 469.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[CH2:2]([C:3]1([CH2:7][OH:8])[NH:4][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:6][CH2:5]1)[OH:1]
Reactant: O=C1CCCCC1
Reactant: NC(CO)(CO)CO
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1(CO)COC2(CCCCC2)N1

Procedure:
Tris-(hydroxymethyl)-aminomethane (24.23 grams; 0.2 mole) and cyclohexanone (19.63 grams; 0.2 mole) were refluxed overnight in 150 mls of toluene, using a water separator to remove approximately 3.6 mls of water. The toluene was then removed by distillation and the residue was recrystallized from acetone to obtain 32 grams (79.5% of theoretical; m.p. 117°-119° C.) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[F:18][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1F
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Nc1ccccc1F
Reaction time: 0.17 h

Procedure:
To 2-fluoroaniline (1.55 g, 13.9 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.56 g, 13.9 mmol) and the reaction stirred for 10 minutes prior to the addition of 2,6-difluoronitrobenzene (2 g, 15.5 mmol) dissolved in anhydrous dimethylformamide (2 mL). Upon disappearance of 2-fluoroaniline the reaction was partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL) and the organics were dried over sodium sulfate. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine as a slightly impure off-white solid (1.5 g, 43%). (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine (1.5 g, 6 mmol) and a spatula tip of 5% Pd/C in methanol (100 mL) were reduced in the parr shaker. Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give 3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine as a brown oil (0.5 g, 38%). MS (ES) m/z 221.1
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CN(C)CCCCCCN
Product: CN(C)CCCCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 6-(dimethylamino)-hexylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1.[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1cccc(Cl)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cccc(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 47.1 %

Procedure:
To a suspension of 3-chloro-phenol (1.65 g, 12.89 mmol) in DMF (10 mL), was added KOH (1.45 g, 25.78 mmol) and the mixture heated at 110° C. for 30 min. The mixture was cooled to 25° C. and 4-fluoro-2-methyl-1-nitro-benzene (0.5 g, 3.22 mmol) was added. This mixture was then heated to 130° C. for 12 h. The reaction mixture was treated with 10% NaOH solution and extracted with EtOAc (3×25 mL). The organic phase was washed with brine (3×5 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica, 0.5% EtOAc in hexanes) to afford 4-(3-chloro-phenoxy)-2-methyl-1-nitro-benzene (400 mg, 47%). MS (M+H)+=263; 1H NMR (CDCl3) δ: 8.05 (d, J=7.1 Hz, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.20 (d, J=5.3 Hz, 1H), 7.06 (s, 1H), 7.03-6.85 (m, 3H), 2.59 (s, 3H).