Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]
Reactant: C/C=C/C(=O)Cl
Reactant: c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1cccc2ccccc12
Yield: 64.3 %

Procedure:
Naphthalene (128 mg), crotonoyl chloride (124 mg), and aluminium chloride (180 mg) were reacted in dichloromethane (1.5 mL) at from −20° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (126 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([OH:13])[CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:4]([CH:1]1[CH2:2][CH2:3]1)[N:5]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Yield: 62.9 %

Procedure:
2-Cyclopropyl-4-hydroxy-1-(phenylmethyl)-1H-indole (316 mg, 1.2 mmol) was alkylated by treating with 0.11 mL (1.2 mmol) of methyl bromoacetate and 48 mg (1.2 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 253 mg (63% yield) of [[2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.O>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([N:10]([CH2:30][CH:29]([CH3:32])[CH3:31])[S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[CH:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2cnc(C3CC3)nc2)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Solvent: O
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2cnc(C3CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of N-(2-cyclopropylpyrimidin-5-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzenesulfonamide (74 mg, 0.185 mmol) in acetonitrile (0.1 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.074 mL, 0.370 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.04 mL, 0.370 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling the reaction was diluted with acetonitrile (0.5 mL) and water (0.5 mL) and the crude sample purified by mass directed autoprep (formic acid modifier) to give the title product (43.75 mg). LCMS (2 min, High pH) Rt 1.27 min, m/z (ES+) 457 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([NH:25][C:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=S)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: Nc1cccc(-c2ncccc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C(F)(F)F)c1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a suspension of 3-(3-trifluoromethylpyridin-2-yl)aniline (200 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (278 mg) and diisopropylethylamine (0.336 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (279 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-trifluoromethylpyridin-2-yl)phenyl)guanidine (234 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]=[O:9]>>[CH3:1][C:2]([CH2:5][CH2:6][CH3:7])([CH2:8][OH:9])[CH2:3][OH:4]
Reactant: C=O
Reactant: CCCC(C)C=O
Product: CCCC(C)(CO)CO

Procedure:
is a known synthetic perfume obtainable from 2-methyl pentanal 23 (cf. following scheme). The educt 23 is reacted with 2 equivalents of formaldehyde in a crossed Canizzaro reaction to form 2-methyl-2-propylpropane-1,3-diol 24. The diol 24 may then be acetalized with 2-methylpentanal 23 to form Troënan® 22.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:26])([OH:25])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:26][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:25][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCC(c3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
(S)-1-(2-Chloro-4-nitro-imidazol-1-yl)-2-methyl-3-(4-phenylpiperidin-1-yl)propan-2-ol prepared in Example 276 (0.703 g, 1.86 mmol) was dissolved in DMF (5 ml). To the solution, sodium hydride (89 mg, 2.23 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added. The precipitates were filtered off, purified by silica gel column chromatography (n-hexane/acetone=3/1) and recrystallized from ethyl acetate to afford (S)-2-methyl-6-nitro-2-(4-phenylpiperidin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole (0.230 g, yield 36%) as a white powder.
Reaction SMILES: FC1C=C(C=CC=1OC)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:29]([CH2:31][CH2:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])=[O:30].[C:48]([O-:51])(=[S:50])[CH3:49].[K+]>C(O)C.O>[C:48]([S:50][CH:31]([C:29](=[O:30])[C:28]1[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:26]([F:25])[CH:27]=1)[CH2:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])(=[O:51])[CH3:49]
Reactant: COc1ccc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)cc1F
Reactant: CC([O-])=S
Agent: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C(CC(=O)N2CCC[C@H]2C(=O)O)SC(C)=O)cc1F

Procedure:
As described in Example 15, the preceding compound is converted to 3-(3-fluoro-4-methoxybenzoyl)propionic acid, hydroxysuccinimide ester and coupled to L-proline as in Example 16. The 1-[3-(3-fluoro-4-methoxybenzoyl)propionyl]-L-proline m.p. 180°-182° C. is brominated as in Example 20 and the product reacted with potassium thioacetate in ethanol-water as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([CH2:52]Br)[CH:45]=1>CC#N>[Br:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([CH:45]=1)[CH2:52][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: COc1ccc(Br)cc1CBr
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: COc1ccc(Br)cc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 89.7 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 4-bromo-2-(bromomethyl)-1-methoxybenzene (500 mg, 1.786 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively by dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (700 mg, 85% yield). 1H NMR (500 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.34-7.29 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.47 (s, 2H), 3.88 (s, 2H), 3.71 (s, 3H), 2.78 (t, J=6.7 Hz, 2H), 1.82 (t, J=6.7 Hz, 2H), 1.38 (s, 9H), 1.34 (s, 6H). LRMS [ESI, MH−] m/z calcd for C25H33BrNO6S 554.12, found 554.1.
Reaction SMILES: [CH:1]1(SC2C=CC(C(C3C=CC(C(F)(F)F)=C(OC)N=3)=O)=CC=2)CC1.[Si]([O:42][CH2:43][C@H:44]([CH3:60])[CH2:45][S:46]([C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[N:51][N:50]=1)(=[O:48])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:54]1([N:53]2[C:49]([S:46]([CH2:45][CH:44]3[CH2:60][CH2:1][O:42][CH2:43]3)(=[O:47])=[O:48])=[N:50][N:51]=[N:52]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CS(=O)(=O)c1nnnn1-c1ccccc1
Product: O=S(=O)(CC1CCOC1)c1nnnn1-c1ccccc1

Procedure:
The title compound was obtained as a white solid (24 mg, 13% (three steps)) by performing substantially the same reaction as in Examples 1-47(1), 1-2 and 1-1(2) sequentially except for using [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 and using 5-{[(2S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]sulfonyl}-1-phenyl-1H-tetrazole obtained in Reference Example 3-15 in place of 1-phenyl-5-[(tetrahydrofuran-3-ylmethyl)sulfonyl]-1H-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([S:24]([C:20]5[S:19][CH:23]=[CH:22][CH:21]=5)(=[O:26])=[O:25])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Product: O=S(=O)(c1cccs1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The same reaction procedure is followed as for the compound of Example 8, using 0.50 g (1.94 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido [3',4':4,5]pyrrolo[3,2-c]quinoline and 0.354 g (1.94 mmol) of 2-thiophenesulfonyl chloride. The reaction solution is diluted with water and is stirred for 2 hours. The resulting precipitate is collected by filtration and triturated with methanol/chloroform/hexane to yield 0.575 g (78%) of the title compound as an off white solid: m.p.>250° C.; m/e 403.
Reaction SMILES: CC1C=CC([N+]([O-])=[O:9])=CC=1O.CN(C)CCO.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:31]1([P:24](=[O:9])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
As another non-limiting example, 2-methyl-5-nitrophenol (2.00 g, 13.07 mmol), N,N-dimethylethanolamine (1.31 mL, 13.07 mmol) and triphenylphosphine (4.46 g, 16.99 mmol) were placed in a 100 mL round-bottomed flask under nitrogen. 40 mL of anhydrous THF were added via syringe at 0° C. After stirring the reaction mixture at this temperature for 10 minutes, 7.32 mL of a solution of diethylazodicarboxylate 40% in toluene (2.93 g, 16.99 mmol) were added via syringe. The reaction was warmed to room temperature and stirred under nitrogen for two hours. The solvents were removed under vacuum. Triphenylphosphine oxide formed during the reaction was precipitated in a mixture of ethyl acetate/hexane and filtrated. The crude was then purified by flash chromatography (0 to 2% of MeOH in DCM) to afford 10 (2.11 g, 70%) as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]([OH:15])=O)([O-:9])=[O:8].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[N+:7]([C:10]1[CH:11]=[C:12]([C:13]2[O:15][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-:9])=[O:8]
Reactant: O=C(O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCCC1

Procedure:
Oxalyl chloride (71 μL; 0.84 mmol; 3 eq.), Intermediate 4 (70 mg; 0.28 mmol; 1 eq.), Intermediate 2 (62 mg; 0.28 mmol, 1 eq.) and DIEA (145 μL; 0.84 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) followed by precipitation in n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: CS(O[CH:6]([CH2:10][CH3:11])[CH2:7][O:8][CH3:9])(=O)=O.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[CH3:9][O:8][CH2:7][CH:6]([N:12]=[N+:13]=[N-:14])[CH2:10][CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(COC)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COC)N=[N+]=[N-]
Temperature: 57.5 °C

Procedure:
A solution of crude mesylate 1 (90.0 g, 0.495 mol) in DMF (500 mL) was treated with NaN3 (48.22g, 0.74 mol, 1.5 equiv) at 25° C. under N2. The resulting reaction mixture was warmed to 55-60° C. for 6-8 h with stirring before being quenched with H2O (500 mL). The pale-yellow solution was then extracted with EtOAc or Et2O (4×200 mL). The combined EtOAc (or Et2O) extracts were washed with H2O (3×500 mL), dried (MgSO4), and concentrated in vacuo. The residual solution was found to contain desired azide 2 (60.3 g, 64.5 g theoretical, 94%), which was found to be pure enough and directly used in the following reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].Cl.[CH3:29][N:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH:32]4[CH2:33][N:30]([CH3:29])[CH2:31]4)=[O:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: CN1CC(N)C1
Agent: Cl
Product: CN1CC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)C1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.06 g) was reacted with 1-methylazetidin-3-amine hydrochloride similar to as described in Example 2 to afford 13.4 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methylazetidin-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 442 (M)+. 1H NMR (400 MHz, DMSO) δ 11.76 (d, J=6.7 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 7.90 (s, 1H), 7.01 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 5.01-4.93 (m, 2H), 4.55-4.49 (m, 2H), 4.37 (dd, J=13.4, 6.7 Hz, 1H), 3.58 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.1 Hz, 2H), 2.24 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:8][CH2:7][CH:6]([CH2:4][O:5][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:18][C:17]2=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3[nH]c4ccc(F)cc4c3C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanol (compound IV of Example 2) (5.975 g, 0.0272 mol) in anhydrous pyridine (15 mL) was cooled in ice bath and treated dropwise under vigorous stirring with an ice cold solution of para-toluenesulfonyl chloride (6.17 g) in anhydrous pyridine (10 mL). After stirring for one hour in the cold, the mixture was placed overnight in the refrigerator. It was then quenched with water (100 mL) under stirring and cooling. After 30 minutes the mixture was extracted with ethyl acetate (3×100 mL). The extracts were washed with cold 3N sulfuric acid (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and evaporated to dryness. The crude material (light brown foam, 9.827 g) was used as such in the next step. MS (ES): [M−H]− @m/z 372.1.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].Cl[CH2:19][C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:22]1[C:21]2[C:26](=[CH:27][C:28]3[C:33]([C:20]=2[CH2:19][S:1][CH2:2][C@H:3]2[O:7][C@@H:6]([N:8]4[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]4=[O:10])[CH2:5][C@@H:4]2[OH:17])=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CS)O2)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CSCc3c4ccccc4cc4ccccc34)O2)c(=O)[nH]c1=O
Yield: 34.8 %

Procedure:
258 mg (1 mmol) of 5'-deoxy-5'-mercaptothymidine was added to 20 ml of acetone. 272 mg (1.2 mmol) of 9-chloromethylanthracene and 1 g of anhydrous potassium carbonate were then added to the solution under an atmosphere of nitrogen. The resulting mixture was then stirred whilst being heated under reflux for 2 hours. At the end of this time, precipitates were filtered off from the reaction mixture, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was crystallized from 10 ml of ethanol, to give 156 mg (yield 35%) of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13]
Reactant: Cc1ccc(C(=O)O)c(NC(=O)Cc2c[nH]c3ccc(Br)cc23)c1
Reactant: OB(O)c1cccs1
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: Cc1ccc(C(=O)O)c(NC(=O)Cc2c[nH]c3ccc(-c4cccs4)cc23)c1
Yield: 4.1 %

Procedure:
2-{[(5-bromo-1H-indol-3-yl)acetyl]amino}-4-methylbenzoic acid (product of example 6, 48 mg), thiophene-2-boronic acid (17 mg), tetrakis(triphenylphosphine)palladium(0) (12 mg) was heated in a mixture of 2M sodium carbonate solution (0.5 ml) and dimethoxyethane (0.5 ml) for 18 h at 80° C. The mixture was concentrated and diluted with DCM, then washed with 2N HCl for 1 hr. The solvent was reduced and the residue purified by mass-directed automated HPLC to give the title compound (2 mg). MH+391.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([N+:26]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH2:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1CCCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C

Procedure:
5-Nitro-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (prepared by the procedure described in Example 2 for the 5-bromo analog) (426 mg) was dissolved in 20 mL of methanol. Palladium on carbon (85 mg) was added and the flask was seal with a rubber septum. A vacuum was pulled through a needle and the void was refilled from a balloon of hydrogen gas. The resulting mixture was stirred under 1 atm of hydrogen gas for 17 h. In the morning, LCMS analysis revealed consumption of the starting material and formation of the product. The reaction mixture was filtered through diatomaceous earth and concentrated under vacuum to yield 5-amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester as an orange foam (432 mg, solvent trapped within). This material was used without further manipulation.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:10][C:11]1[C:17](F)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.O>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:17]1[C:11]([F:10])=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[C:14]([NH2:15])[CH:16]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a 250 ml three-necked flask under an argon atmosphere, 5.3 g of 3-dimethylamino-1-propanol, in solution in 100 ml of tetrahydrofuran, are cooled to 0° C. using an ice bath and then introduce 2.3 g of sodium hydride at 50% in liquid petroleum jelly. After stirring for 1 hour at 0° C., rapidly add a solution of 3 g of 4,5-difluoro-2-nitroaniline in 100 ml of tetrahydrofuran and then heat in the region of 70° C. for 1 hour. The reaction mixture is poured into 100 ml of water and extracted with three times 100 ml of ethyl acetate. The organic phase is dried over magnesium sulphate and brought to dryness under reduced pressure. The solid obtained is washed with pentane, filtered, and dried under a hood. In this way, we obtain 3.5 g of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine, in the form of a yellow solid with the following characteristics: