Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=O)=[C:17]([Cl:27])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](=[O:24])[N:3]([CH2:1][CH3:2])[C:4]3[N:5]=[C:6]([S:12][CH3:13])[N:7]=[CH:8][C:9]=3[CH:10]=2)=[C:17]([Cl:27])[CH:16]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: CCOC(=O)Cc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(SC)nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 4-ethylamino-2-(methylthio)pyrimidine-5-carbaldehyde (9, 1.00 g, 5.07 mmol) in anhydrous dimethylacetamide (10 mL) was added ethyl 4-bromo-2-chlorophenylacetate (1.70 g, 6.12 mmol) and cesium carbonate (3.30 g, 10.13 mmol). The reaction mixture was stirred at 100° C. for 2 h. The mixture was poured into ice water and the orange solid was collected, washed with water, dried and purified by Teledyne-Isco using a hexane:ethyl acetate gradient (1:0→4:1) to afford the title compound as a white solid (0.30 g, 0.73 mmol, 14%). ESMS m/z 410 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.3, 1.5 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(-c2cccc(N)c2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-ethoxyphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 68% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20].B(O)(O)O>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:17][C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:3][CH:2]([CH3:18])[CH3:1])=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30° C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@H:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:36](C(C)C)CC)(C)C.CN(C(O[N:50]1N=NC2[CH:53]=[CH:54][CH:55]=[N:56][C:51]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.N1CCCN=C1N>[C:29]([O:28][C:26](=[O:27])[C@@H:11]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:36][C:51]2[NH:50][CH2:53][CH2:54][CH2:55][N:56]=2)=[CH:15][CH:14]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1=NCCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
88 mg of 4-[4-((2S)-2-benzenesulfonylamino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in tetrahydrofuran and 22.6 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine, 123 mg of diisopropylethylamine and 79.4 mg of HATU were added. The reaction mixture was stirred overnight, and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on reversed-phase (C-1 8) silica gel eluting with a gradient of 10-90% acetonitrile in water. Yield 40.1 mg. MS (FAB+): m/e=545.3 (M+H)+.
Reaction SMILES: [Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17]O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1.[Cl-:38].[Li+]>CN(C)C=O.O>[Cl:1][C@:2]12[C@@H:22]([Cl:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][Cl:38])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH:4]=[CH:5][C:6](=[O:36])[CH:7]=1
Reactant: [Cl-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](Cl)[C@@]12Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](Cl)[C@@]12Cl

Procedure:
A solution of 9,11β-dichloro-17,21-dihydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, 21-methanesulfonate (1 mmole) in 20 ml of dimethylformamide is heated at 80°C for 3 hours with 1 g of lithium chloride, cooled, diluted with water and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C:17]#[N:18])[C:7]3=4.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][CH2:17][NH2:18])[C:7]3=4
Reactant: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 82 °C
Yield: 27.9 %

Procedure:
To a mixture of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.2838 g, 0.757 mmol) in dry THF (10 mL) is added borane-methylsulfide complex (0.22 mL, 2.27 mmol). The mixture is refluxed under an argon atmosphere at 82° C. for 18 h. The mixture is then cooled to room temperature and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in methanol (10 mL), CH2Cl2 (5 mL), and conc. HCl (3 mL) and heated at 60° C. for 1 h. The mixture is neutralized with aqueous potassium carbonate and partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate and concentrated. Column chromatography (50 g silica gel) using CH3OH/CH2Cl2 (4/96) as eluent gave 0.080 g (28%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine; mp 127-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrCCCCBr
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(N2CCCC2)cc1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g), 1,4-dibromobutane (2.59 g), potassium carbonate (0.35 g) and potassium iodide (0.5 g) in DMF (10 ml) was heated at 80° C. for 5 hours under stirring, and then evaporated in vacuo. After addition of 30% aqueous methanol to the residue, the resulting precipitates were collected by filtration and recrystallized from a mixture of methanol and chloroform (7:3) to give 6-(4-pyrrolidinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.65 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[N+]=[N-].C(#N)C>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:23])[CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Solvent: CC#N
Solvent: O
Product: NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 17-azido-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2(g)-Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14](=[N+]=[N-])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1=Nc2ccccc2C1=[N+]=[N-]
Product: CCOC(=O)c1[nH]c2ccccc2c1Oc1ccccc1
Yield: 78 %

Procedure:
React 3-diazo-3H-indole-2-carboxylic acid ethyl ester, 5, (300 mg, 1.38 mmol) with phenol (5.0 equiv., 650 mg, 6.90 mmol) as described in General Synthetic Procedure VIII. Purify by flash chromatography to afford 3-phenoxy-1H-indole-2-carboxylic acid ethyl ester 6 (R1=phenyl, 303 mg, 78%) as a yellow solid. Hydrolyze the ester to the carboxylic acid 7 (R1=phenyl) using General Synthetic Procedure IX and then transform the carboxylic acid to the corresponding primary amide as described in General Synthetic Procedure V to afford the title compound Il as a light purple solid, tlc (silica gel) Rf=0.15.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=3[CH3:27])[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].CN[CH2:37][C:38]([OH:40])=[O:39].C(Cl)Cl>CO.C(O)(=O)C>[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:2]([CH3:1])[CH2:37][C:38]([OH:40])=[O:39])=[CH:21][C:20]=3[CH3:27])[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]
Reactant: [BH3-]C#N
Reactant: COCc1cc(-c2nc(-c3ccc(C=O)cc3C)no2)ccc1-c1ccccc1C
Reactant: CNCC(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)cc3C)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (29.7 mg; 0.47 mmol) was added into a solution of 4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)-3-methylbenzaldehyde (185 mg, 0.43 mmol) and 2-(methylamino)acetic acid (65 mg, 0.87 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (75 μl). The mixture was stirred at room temperature overnight and the solvent was then removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a pale yellow gum. 1H NMR (DMSO-d6, 400 MHz) δ 8.37-8.32 (1H, m), 8.20 (1H, dd, J=7.8, 1.9 Hz), 8.06 (1H, d, J=7.7 Hz), 7.47-7.37 (5H, m), 7.38-7.29 (1H, m), 7.18 (1H, d, J=7.3 Hz), 4.23 (2H, m), 3.78 (2H, s), 3.28 (3H, s), 3.25 (2H, s), 2.67 (3H, s), 2.34 (3H, s), 2.07 (3H, s). LC/MS (Method A): 472 (M+H)+. HPLC (Method F) Rt 3.19 min (Purity: 99.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:6]([OH:8])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:30][O:29][C:25]1[CH:24]=[C:22]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:21]=[C:20]([O:19][CH3:18])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
Compound 64 is synthesized following a similar method as in Example 1 and using 3-methoxy-4-aminobenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 57%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]3[CH2:14][N:13]([C:6]=2[CH:5]=1)[CH2:12][CH2:11][NH:10]3)([O-:3])=[O:2].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)(O)[O-].[Na+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:19]([N:10]1[CH:9]2[CH2:14][N:13]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:7]=3[CH2:8]2)[CH2:12][CH2:11]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCNC(C2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (17.5 g.), allyl bromide (7.6 ml.), sodium bicarbonate (1 teaspoon) and N,N-dimethylformamide (200 ml.) was stirred overnight at room temperature, then concentrated to dryness. The residue was partitioned between dilute aqueous sodium hydroxide and isopropyl acetate. The isopropyl acetate layer was washed with dilute aqueous sodium hydroxide and brine, filtered and concentrated to dryness. The residue was recrystallized from isopropyl alcohol, and the product was combined with corresponding product (2.3 g.) from a previous a preparation. Ethereal hydrogen chloride was added to a solution of the combined products in ethyl acetate affording 4-allyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (10 g.), the compound of Formula IV wherein Q is allyl.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]Cl)[CH:2]=[CH2:3].[NH3:13]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH2:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1CCl
Reactant: N
Product: C=CCOc1ccccc1CN

Procedure:
3.0 g (16.4 mmol) of the compound from Example I are boiled under reflux for 17 hours in 250 ml of a saturated methanolic ammonia solution. The reaction mixture is evaporated in vacuo, the residue is taken up in methanol and the mixture is evaporated again; this process is repeated a few times. The crude product is taken up in dichloromethane and extracted several times with water. The aqueous phase is evaporated to a very great extent, an oil being obtained which crystallizes on standing.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[CH:14]([C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])([CH3:16])[CH3:15].[S:30](=[O:32])=[O:31].[NH3:33]>CCOCC.O1CCCC1>[NH2:33][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])(=[O:32])=[O:31]
Reactant: CCN(CC)C(=O)c1ccccc1C(C)C
Reactant: O=S=O
Reactant: N
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c(C(C)C)cccc1S(N)(=O)=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of N,N,N',N'-tetramethylethylenediamine (25.5 g) in anhydrous ether (600 mL) was added s-butyllithium (1.3M, 170 mL) and the mixture was cooled to -70° C. under nitrogen. A solution of 2-isopropyl-N,N-diethylbenzamide (44 g) in anhydrous ether (300 mL) was added dropwise over 20 minutes. The temperature was maintained at or below -60° C. during the addition. After the addition the mixture was stirred at -70° C. for 30 minutes, allowed to warm to -50° C. during 30 minutes, held at -50° C. for 10 minutes, then cooled back to -70° C. By cannulation tube a solution of sulfur dioxide (50 g) in anhydrous ether (50 mL) precooled to -60° C. was added under positive nitrogen pressure over a 10-minute period. The temperature of the reaction mixture during the addition was maintained below -50° C. A white powdery precipitate of aryllithium sulphinate separated out almost immediately. The temperature was allowed to rise to room temperature during one hour. Sulfuryl chloride (54 g) was added dropwise with continued stirring during 15 minutes. After further stirring for 30 minutes at 0°-5° C. a white precipitate was filtered off and washed with anhydrous ether (2 L). Removal of the solvent under vacuum gave a faint yellow oil, which was dissolved in tetrahydrofuran (150 mL). The solution was cooled to 0° C. and concentrated aqueous ammonia (28%, 60 mL) was added in portions over 15 minutes. The temperature was kept at 10° C. or below throughout the addition. After stirring for 15 minutes at ambient temperature the tetrahydrofuran and excess ammonia were removed and the residue was acidified with hydrochloric acid (2N) to pH 1. The resulting white solid was collected, washed with water (200 mL) and hexane (200 mL) and dried affording 2-aminosulfonyl-6-isopropyl-N,N-diethylbenzamide (54 g, 90 % yield).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:36])[CH2:35][CH2:34]2)[CH:30]=[C:29]([F:37])[C:28]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:44](=[O:45])[C:42]2[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:28]3[C:29]([F:37])=[CH:30][C:31]([C:33]4([OH:36])[CH2:34][CH2:35]4)=[CH:32][C:27]=3[F:26])[N:43]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 204. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.27 (dd, J=8.7, 4.0 Hz, 1H), 8.13 (t, J=8.9 Hz, 1H), 7.90 (s, 1H), 7.09 (d, J=9.8 Hz, 2H), 6.26 (s, 1H), 4.81 (dd, J=10.5, 3.7 Hz, 1H), 4.34-4.09 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.12-2.99 (m, 1H), 2.11-1.99 (m, 1H), 1.83-1.53 (m, 5H), 1.27-1.08 (m, 4H). LCMS (ES+) m/z 520 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])(=[O:11])=[O:10])=[C:5]([CH3:26])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[CH3:25])(=[O:10])=[O:11])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCNC[C@@H]1C
Yield: 91.5 %

Procedure:
A solution of 1,1-dimethylethyl (3S)-4-[(4-cyano-2-methylphenyl)sulfonyl]-3-methyl-1-piperazinecarboxylate (may be prepared as described in Description 16) (3.71 g, 9.78 mmol) and TFA (5.00 ml, 64.9 mmol) in dry DCM (15 ml) was stirred at rt for 1 h, then concentrated under vacuum, azeotroping with toluene (25 ml). The residue was dissolved in MeOH (20 ml) and added to an SCX-2 cartridge (50 g), washing with MeOH. The product was eluted with 2M NH3 in MeOH; concentration under vacuum gave the title compound as a white solid (2.50 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.O>CN(C=O)C>[NH3:10].[C:3]([O:7][C:8](=[O:26])[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[N:18]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[N:17]=2)[CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(Br)ccc23)CC1
Product: N
Reaction time: 16 h

Procedure:
Sodium hydride (42 mg of a 60% dispersion in oil, 1.05 mmol) was added to a stirred solution of [4-(6-bromo-1H-indazol-3-yl)-piperidin-1-yl]-acetic acid tert-butyl ester (332 mg, 0.84 mmol) in DMF (7 ml) and after 30 min, a solution of 4-fluorobenzyl bromide (0.105 ml, 0.84 mmol), in DMF (7 ml) was added. The mixture stirred at +23° under nitrogen for 16 h, treated with water (25 ml), extracted with ethyl acetate (3×50 ml) and the combined, dried (Na2SO4) organic extracts were evaporated in vacuo to give an oil. This oil was purified by flash chromatography over silica gel (Merck 9385) eluting with dichloromethane--ethanol--880 ammonia (967:30:3) to give impure title compound. This was further purified by flash chromatography over silica gel (Merck 9385) eluting with ethyl acetate--cyclohexane (1:2) to give the title compound as a colourless oil (290 mg).