Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)[CH3:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:19][CH:18]=3)=[O:21])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 40b), from 5-[[1-(1-methylethyl)-4-piperidinyl]oxy]-1H-Indole-2-carboxylic acid and 1-(tert-butoxycarbonyl)piperazine. Light-yellow solid. MS (m/z): 471.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.3 g, 10.0 mmol) was dissolved in DMF (66 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.31 g, 10.0 mmol), triethylamine (2.8 mL, 20.0 mmol) and TBTU (3.5 g, 11.0 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized with MeOH to afford the title compound (2.4 g) as a yellow solid. 1HNMR (500 MHz, DMSO-D6) δ 8.53 (s, 1H), 7.81 (d, J=4.0 Hz; 1H), 7.75-7.54 (m, 5H), 3.69 (m, 2H), 3.44 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H). LCMS: m/e 436 (M+H)+, ret time 1.73 min (method 2).
Reaction SMILES: [Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1c(F)cc(Cl)c(F)c1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl

Procedure:
13.7 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)acetate are heated under reflux with 10.25 g of triethyl orthoformate and 11.8 g of acetic anhydride for 2 hours. The mixture is then concentrated in vacuo up to a bath temperature of 140° C. and 15.7 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are obtained as an oil, nD25 : 1.5302.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(O[N:44]1[C:49](=[O:50])[CH2:48][CH2:47][C:45]1=[O:46])=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][N:44]2[C:49](=[O:50])[CH2:48][CH2:47][C:45]2=[O:46])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
4-(9-Carboxynonyloxy)benzoic acid tert-butyl ester (779 mg, 2.14 mmol) was dissolved in THF (15 mL), and DIEA (366 μl, 2.14 mmol) was added. The mixture was cooled to 0° C., and placed under nitrogen, and HSTU was added. The mixture was stirred at 0° C. for 30 min and at RT for 16 h. The sample was concentrated under vacuum and AcOEt (40 ml) was added. The mixture was washed with 0.2 N HCl (2×25 ml), dried over MgSO4, and concentrated under vacuum to yield a slightly yellow solid. The solid was recrystallized from AcOEt to yield a white powder (276 mg, 28% yield). The mother liquor was concentrated to yield crystalline residue (430 mg, 43% yield). Data for the white powder:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1.C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:25])C>O>[CH:1]1[N:5]2[C:6]3[C:12]([CH:23]=[O:25])=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1
Reactant: CC(=O)O
Reactant: c1cc2c(ncc3nncn32)[nH]1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc3nncn3c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Water (1.0 mL) was added to a mixture of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.200 g, 1.26 mmol, prepared using D from Preparation #BBBBB.1 and NaOH) and hexamethylenetetramine (0.264 g, 1.89 mmol). Acetic acid (0.5 mL) was added. The reaction vessel was sealed and the mixture was warmed to about 100° C. After about 8 h, the solution was allowed to cool to ambient temperature. After sitting for about 13 h, the mixture was cooled to about 0° C. The resulting mixture was diluted with water (1 mL) and then filtered rinsing with water. The solid was dried to afford 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.041 g, 18%): LC/MS (Table 1, Method n) Rt=0.23 min; MS m/z 188 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[O:30][CH:31]=[CH:32][N:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[O:30][CH:31]=[CH:32][N:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Yield: 44.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(oxazol-2-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.17 mmol) obtained in step 2 and methanesulfonamide (0.081 g, 0.850 mmol), the title compound (0.04 g, 46%) was obtained.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[CH3:15].O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:11])=[CH:8][C:7]=1[CH3:15]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
AlCl3 (3.63 g, 27.2 mmol) was added portionwise to 4-bromo-3-methylbenzoyl chloride (5.30 g, 22.7 mmol) dissolved in anisole (7 mL) at 0° C. The reaction mixture was warmed to RT, stirred for 1 h, and then cooled to 0° C. Water (200 mL) was cautiously added dropwise, and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (250 mL), brine (250 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 6.42 g (93%) of 65 as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 1H), 7.62 (m, 2H), 7.79 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:30]1[CH:31]=[C:26]([CH:22]2[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(Cl)cc(Cl)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (58 mg, 0.22 mmol) and of crude 2-bromo-6-(3,5-dichloro-phenyl)-cyclohexanone (75 mg, 0.23 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (30 mg, 28%) as a yellow solid. MS ISP (m/e): 485.3/487.3 (100/72) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 7.11 (d, 1H), 7.04 (s, 2H), 6.84 (s, 1H), 6.69 (d, 1H), 3.98 (m, 1H), 3.63 (s, 3H), 2.75 (m, 2H), 2.30 (s, 3H), 2.22 (m, 1H), 1.83 (m, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[C:27][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cn1
Yield: 34 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 34% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and 3,3-dimethyl-1-butyne. Purification by column chromatography, using 10 to 60% ethyl acetate in heptane as the eluent.
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.[C:12]1([CH2:18][O:19][NH:20][CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH:10]([N:20]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[O:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=Cn1nnc2ccccc21
Reactant: CCCC[C@H](CNOCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 1H-1,2,3-benzotriazole-1-carbaldehyde (26 g, 0.18 mol) in THF (200 ml) at 0° C. was added dropwise a solution of (2R)-2-({[(phenylmethyl)oxy]amino}methyl)hexanoic acid (8) (40 g, 0.16 mol) in THF (200 mL). The reaction mixture was warmed up to rt and stirred overnight. LC/MS indicated completion of the reaction. To the reaction mixture at 0° C. was added water (400 mL), Na2CO3 (36 g), and Boc2O (43.6 g, 0.36 mol). The mixture was stirred for 3 h. THF was removed under vacuum. The aqueous mixture was washed with ether and then acidified to pH ˜2.0 with acetic acid, and extracted with ethyl acetate. The extracts were dried and concentrated to provide the title compound (36.8 g, 80%). LCMS: (M+H)+: 280.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:19](OS(C)(=O)=O)[CH3:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].C1OCCOCCOCCOCCOC1.CCOC(C)=O>CN(P(N(C)C)(N(C)C)=O)C>[N:26]([CH:19]([CH3:20])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[N+:27]=[N-:28]
Reactant: CC(OS(C)(=O)=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of mesylate 108 (500 mg, 1.26 mmol) in HMPA (2 mL), NaN3 (409 mg, 6.29 mmol) and 15-crown-5 ether (252 mg, 1.26 mmol) were added. The solution was stirred at 55° C. for 3 h. The reaction mixture was added to EtOAc (30 mL), washed with brine (10 mL), dried (Na2SO4) and evaporated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/15) to afford azide 109 (160 mg, 34%) as a colorless oil. Rf 0.33 (AcOEt/Hexanes 1/15). [α]D20=−46.6 (c=0.4, CHCl3). 1H-NMR (500 MHz, CDCl3): 0.04 (s, 6H), 0.88 (s, 9H), 1.32 (d, J=6.7 Hz, 3H), 1.48 (s, 9H), 3.51-3.61 (m, 1H), 4.75-4.90 (m, 2H), 4.50-4.62 (m, 1H). 13C-NMR (125 MHz, CDCl3): −5.5, 14.1, 16.5, 25.8, 28.3, 31.6, 55.2, 57.2, 62.4, 174.3. IR (neat) 3326.1, 2954.0, 2931.1, 2857.9, 2359.9, 2107.2, 1718.2, 1005.7, 1471.2, 1366.0, 1254.5, 1167.7, 1098.0, 838.1.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(OCC)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:20]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([OH:11])[C:10]=1[CH2:9]2
Reactant: Oc1cccc2c1CC=CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Oc1cccc2c1CC1OC1C2

Procedure:
prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30°C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##SPC33##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-aminobenzoate (30.23 g, 200 mmol) was added to a mixture of iodine (60.91 g, 240 mmol) and silver sulfate (81.07 g, 260 mmol) in 1 L of ethanol at room temperature. The mixture was stirred at room temperature for 18 hours, filtered over Celite and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (230–400 mesh) and eluted with 1% ethyl acetate in hexane to give 35 g (63%).
Reaction SMILES: Br[C:2]1[C:3](C2C=CN=CC=2)=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=1.[CH2:29]([O:36]/[N:37]=[C:38]1\[CH2:39][CH2:40][C:41]2[C:46]\1=[CH:45][CH:44]=[C:43](B(O)O)[CH:42]=2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:29]([O:36]/[N:37]=[C:38]1\[CH2:39][CH2:40][C:41]2[C:46]\1=[CH:45][CH:44]=[C:43]([C:2]1[CH:3]=[N:4][N:5]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:11][CH2:12]3)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:42]=2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(n2cc(Br)c(-c3ccncc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(n2ncc(-c3ccc4c(c3)CC/C4=N\OCc3ccccc3)c2-c2ccncc2)CC1
Temperature: 80 °C
Yield: 166.1 %

Procedure:
To benzyl 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.32 g; Example 5, Step 1) in 10 mL acetonitrile and 3 mL water was added 0.315 g (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (prepared as described in example 2, step 4) and 0.30 g potassium carbonate. The reaction mixture was purged with nitrogen and 84 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The reaction mixture heated to 80° C. for 2 hours, filtered through celite, and the filter cake was washed with acetonitrile. The filtrate was evaporated under vacuum to yield crude product. The residue was purified by chromatography, eluting with ethyl acetate to afford 0.36 g (83% yield) product as a colorless oil. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 598.3 by positive ESI.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=O.[CH3:18][O:19][C:20](=[O:27])[CH2:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=O>>[CH3:18][O:19][C:20]([C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)=[O:27]
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1F
Reactant: COC(=O)CC(=O)C1CC1
Product: COC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4-chloro-phenyl)-(2-fluoro-phenyl)-methanone and 3-cyclopropyl-3-oxo-propionic acid methyl ester. White solid. MS (ESI): 356.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](Cl)=[S:26].O.[NH2:29][NH2:30].O>O1CCCC1>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:26])[NH:29][NH2:30]
Reactant: NN
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)Cl)OCO3
Solvent: O
Solvent: C1CCOC1
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reaction time: 1 h
Yield: 90.2 %

Procedure:
1.0 g (2.47 mmol) of carbothioyl chloride XI was added to a stirred solution of 0.37 g (7.42 mmol) of hydrazine hydrate in 15 ml of tetrahydrofuran at 5-10° C. over a period of about 0.5 h, then after 1 h stirring, the mixture was poured into water and the precipitated product was filtered off to yield 0.89 g (90%) of the crude product. After drying, it was used in the further reaction steps. The melting point of the product after recrystallization from ethanol was 196° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O)([O-])=O>C(O)C>[N:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: O=Cc1nccn1Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: c1ccc2c(c1)Cn1ccnc1CN2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole-2-carboxaldehyde is dissolved in 150 ml of hot ethyl alcohol, cooled to room temperature and filtered. To the filtrate is added 0.5 g of 10% Pd/C and the mixture hydrogenated at 48 psi for 4 hours. An additional 0.5 g of 10% Pd/C is added and hydrogenation continued for 25 hours at 65 psi. The mixture is filtered through diatomaceous earth and the cake washed with ethyl acetate. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, treated with activated carbon, filtered through diatomaceous earth and hexanes added to the filtrate at the boil to give 1.86 g of the desired product as a crystalline solid, m.p. 164°-170° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH2:19]1[O:21][CH2:20]1>ClCCl>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][OH:21])[CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: C1CO1
Solvent: ClCCl
Product: OCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 0 °C
Yield: 99.6 %

Procedure:
4-(4-(trifluoromethoxy)phenoxy)piperidine (1.31 g, 5.0 mmol) was dissolved in dry dichloromethane (30 mL), cooled to 0° C. in ice salt-bath, added ethylene oxide (2.55 mL, 50 mmol), reacted for 3 h in ice salt-bath, stopped the reaction, the reaction was monitored by TLC, the system was spun dry after complete reaction to give 1.52 g title compound, yield was 100%.
Reaction SMILES: N([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1)=[N+]=[N-].C1C(=O)N([Br:43])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:43][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[N:16]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[N:14][N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CBr)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
5-(2-Azidomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole: To 114A (4 g, 9.15 mmol) in chloroform (20 mL) was added NBS (1.711 g, 9.61 mmol) and benzoyl peroxide (30 mg, 0.124 mmol) and the reaction was heated at reflux overnight. Additional NBS and peroxide were added and the reaction was heated an addition 2 h. The reaction was cooled to rt, filtered, and purified by flash chromatography to give 5-(2-bromomethyl-4-chloro-phenyl)-1-trityl-1H-tetrazole (3.5 g, 74.1%). 1HNMR (400 MHz, CDCl3) δ: 4.78 (s, 2H), 7.04-7.14 (m, 5H), 7.24-7.35 (m, 11H), 7.40 (d, J=2.02 Hz, 1H), 8.06 (d, J=8.34 Hz, 1H). This intermediate (1.57 g, 3.04 mmol) and sodium azide (0.198 g, 3.04 mmol) in DMF (8 mL) were stirred for two days. The reaction was partitioned with EtOAc/water/brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and purified by flash chromatography to give 114B. LCMS m/z 195.2 (M+H—N3)+; 152.1 (M+H—N6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH2:25][NH2:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH2:25][NH:26][C:30](=[O:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2cc3nccc(-c4cccc(CN)c4)c3o2)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(-c2cc3nccc(-c4cccc(CNC(C)=O)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 45 %

Procedure:
3-[2-(3,4,5-Trimethoxy-phenyl)-furo[3,2-b]pyridin-7-yl]-benzylamine (0.036 mmol) is dissolved in acetic acid (1.00 ml) and acetic acid anhydride (0.159 mmol) is added. The reaction solution is stirred 4 d at RT. Water is added and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The product is isolated after removal of the solvent in vacuo as yellow solid (45% yield). HPLC (method A): Rt 2.52 min (purity 99.4%); LCMS (ESI+) (method E): Rt 1.87 min, M+H+ 433.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.57 (d, J=5.1, 1H), 8.44 (t, J=5.7, 1H), 8.09 (d, J=12.1, 1H), 7.97 (d, J=7.8, 1H), 7.76 (d, J=2.8, 1H), 7.69-7.56 (m, 2H), 7.44 (t, J=9.5, 1H), 7.33 (d, J=7.8, 2H), 4.39 (d, J=5.9, 2H), 3.91 (d, J=11.1, 6H), 3.78-3.70 (m, 3H), 1.91-1.77 (m, 3H).