Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9]2)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9]2
Reactant: CCOC(=O)c1ccc2c([N+](=O)[O-])cccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(N)cccc2c1
Yield: 100 %

Procedure:
A suspension of ethyl 5-nitro-2-naphthoate prepared according to Price, et al. J. Am. Chem. Soc. 74, 3652 (1952) (8.0 g, 0.0326 mol) in EtOH (200 mL) was hydrogenated over 10% Pd/C (600 mg) at 50 psi for 3 hours 30 minutes. The mixture was filtered through Solka floc and concentrated to give a yellow solid (7.0 g, 100%), m.p. 94°-95° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)[CH2:5][CH2:4]1.[F:29][C:30]1[C:43]([N:44]=[C:45]=S)=[C:42]([F:47])[CH:41]=[CH:40][C:31]=1[CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].CC(C)N=C=NC(C)C>CN(C=O)C>[F:28][C:2]([F:27])([F:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:19]3[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]3)=[CH:13][C:14]3[NH:18][C:45]([NH:44][C:43]4[C:42]([F:47])=[CH:41][CH:40]=[C:31]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])[C:30]=4[F:29])=[N:17][C:15]=3[CH:16]=2)=[O:26])[CH2:7][CH2:8]1
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(F)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)cc3[nH]2)c1F

Procedure:
The title compound is prepared in analogy to 2c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-(4-fluoro-piperidinyl)-4,5-diamino-benzoic acid amide (50 mg, 0.12 mmol), and N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (70 mg, 0.24 mmol), DIC (30 μL) and DMF (2.0 mL).
Reaction SMILES: [BH4-].[Li+].[C:3]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[C:3]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(CO)CC1

Procedure:
A solution of lithium borohydride in tetrahydrofuran (2 M, 0.95 mL, 1.9 mmol) was added dropwise to a solution of ethyl 1-benzoylpiperidine-4-carboxylate (1 g, 3.8 mmol) in tetrahydrofuran (10 mL) with stirring under a nitrogen atmosphere. The reaction mixture was stirred for 18 h, poured onto water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethylacetate) afforded 1-benzoyl-4-hydroxymethylpiperidine, a solid (522 mg, Rf =0.14): m.p. 85°-87° C.; 'H-NMR (CDCl3, 200 MHz): 7.45-7.35 (m, 5H), 4.8-4.6 (m, 1H), 3.9-3.7 (m, 1H), 3.5 (br s, 2H), 3.2-3.6 (m, 3H), 2.25 (br s, 1H), 2.0-1.6 (m, 3H), 1.4-1.0 (m, 2H); HRMS: Calcd. for C13H17NO2 :219.1259; Found: 19.1245.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:29][CH:30]([NH2:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:32][CH:30]([CH3:31])[CH3:29])[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CC(C)N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)Nc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 2 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). 2-Propanamine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further 2-propanamine (0.022 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, 2-propanamine (0.02 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time 2-propanamine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (2.1 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9](=O)[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.8 %

Procedure:
To a 5 L 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 1.6 L of acetic acid and 80.0 grams (0.62 moles) of 3-amino-2-chloropyridine. The mixture was agitated for approx. 10 minutes at 25° C. for dissolution. To the resulting solution was charged 105.9 grams (119.3 mL/0.78 moles/1.25 equivalents) of o-anisaldehyde (2-methoxybenzaldehyde), upon which was obtained a yellow solution after stirring 10 minutes at 25° C. Over a 30 minute period in portions were added 263.7 grams (1.24 moles, 2.0 equivalents) sodium triacetoxyborohydride, while maintaining a temperature of 20° C. The mixture was stirred for 12-18 hours and concentrated to a semi-solid, which was partitioned between methylene chloride and water (800 mL each). The pH was adjusted to 9.5 with 700 mL 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. by cooling. The layers were separated, the aqueous layer was washed with methylene chloride (3×300 mL each), and the methylene chloride layers were combined. The organic layer was washed with 300 mL of saturated sodium chloride solution, and then dried with magnesium sulfate for 30 minutes. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, leaving an off white tacky material (174 grams). The product was reslurried in 120 mL of fresh ethyl acetate at 0°-5° C. for 1.5 hours, filtered, washed with cold ethyl acetate and dried, giving 133.2 grams (86.1%) of the title compound. M.P. 121°-125° C. 1H NMR (CDCl3) δ 7.70 (dd, 1H, J=1 Hz, 2 Hz), 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 3H), 4.95 (t, 1H), 4.40 (d, 2H, J=6), 3.85 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH:13]1[C:21](=[O:22])[C:19](=[O:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15].Cl>C(O)C>[OH:20][C:19]1([C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:10][CH:9]=2)[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: c1ccc(-n2cccc2)cc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(O)(c2cccn2-c2ccccc2)C(=O)N1
Yield: 80.6 %

Procedure:
1-Phenylpyrrole (1.4 g., 0.01 mole), alloxan hydrate (1.6 g., 0.01 mole) and 50 ml. of ethanol were combined and refluxed for 15 minutes. No reaction was noted by tlc. 1 N Hydrochloric acid (10 ml., 0.01 mole) was added and the acidified mixture refluxed for 15 minutes. Incomplete reaction was noted by tlc. A second portion of alloxan hydrate (1.6 g., 0.01 mole) was added and the mixture refluxed another 15 minutes, cooled and evaporated to dryness. Trituration of the residue with water gave title product [2.3 g.; m/e 285; m.p. 232°-234° C. (dec); Rf 0.3 (1:1 ethyl acetate:hexane)].
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C@H:27]12[NH:34][CH2:33][C@H:32]1[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2>C(Cl)Cl>[F:1][C:2]1[C:3]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:34]1[C@H:27]2[C@H:32]([CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2)[CH2:33]1)=[O:7]
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3cccc(F)c3-n3nccn3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 125.7 %

Procedure:
To 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (390 mg, 1.9 mmol) in CH2Cl2 (18 mL) at 0° C. was added DMF (15 μL, 0.2 mmol) and oxalyl chloride (190 μL, 2.3 mmol). After 20 min, the 0° C. ice bath was removed and the reaction allowed to warm to rt. After 30 min the mixture was concentrated, diluted with CH2Cl2 (9 mL) and added to (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) in CH2Cl2 (9 mL) and TEA (390 μL, 2.9 mmol). After judged complete by TLC and LC-MS, the reaction was diluted further with CH2Cl2 and washed with 1 N KHSO4. The aqueous layer was with CH2Cl2. The combined organics were dried (Na2SO4) to give a yellow foam. Purification via silica gel using 40-100% EtOAc in hexanes gave 656 mg (86%) of the title compound as a colorless oil. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.0 [M−C(CH3)3]+.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH3:29])[C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH2:38]([C@H:45]([CH2:49][C:50]([N:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH3:53])=[O:51])C(O)=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([C@H:45]([CH2:49][C:50]([N:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH3:53])=[O:51])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH3:29])[C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Product: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Yield: 32.4 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 252 mg (0.468 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-methyl-N-propylhexanamide [prepared as described in Example 18(a)] and 152 mg (0.488 mmole) of 2(R)-benzyl-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 111 mg of the title compound as a colorless powder, melting at 115°-118° C.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].[NH2:13][C:14]([NH2:16])=[O:15].CC#N>CN(C=O)C>[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][C@@H:12]12)=[O:6]
Reactant: COC(=O)N1C=CC=CC1
Reactant: NC(N)=O
Agent: BrBr
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)N1CC=C[C@H]2OC(N)=N[C@H]21
Yield: 49.9 %

Procedure:
A solution of Br2 (1 ml, 19.3 mmol, 1 equiv.) in DMF (5 ml) is added over 20 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (2.68 g, 19.3 mmol, 1 equiv.) and of urea (2.3 g, 38.6 mmol, 3 equiv.) in a mixture of DMF (19 ml) and of CH3CN (6 ml) at ambient temperature and under argon. The reaction being complete from the end of the addition of the bromine, the reaction mixture is concentrated to dryness. The residue is dissolved in methanol (30 ml), poured onto ice-cold water (150 ml) and then filtered through a Buchner funnel. The filtrate is basified (5% Na2CO3) until a pH of greater than 10 is obtained. After extracting with dichloromethane (4×100 ml), the aqueous phase is saturated with NaCl and then reextracted with dichloromethane (4×100 ml). After drying over MgSO4 and evaporating the solvent, the solid obtained (5.94 g) is chromatographed on silica gel using dichloromethane (DCM) saturated with ammonia and then DCM saturated with NH3:MeOH, 98:2. The product is obtained in the form of a beige solid (1.9 g, 50%).
Reaction SMILES: [OH:1][C@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@@H](C)O
Yield: 45.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.882 mmol, 246 mg) and using dry DMF (2 ml) as the solvent. After the reaction was finished, DCM was added and the reaction mixture was concentrated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 177.8 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.00-1.10 (m, 6H), 2.34 (s, 3H), 3.69-3.90 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.91-7.96 (m, 1H), 8.00 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[F:20][CH2:21][C:22]([CH2:26][F:27])([OH:25])[C:23]#[CH:24]>>[F:19][C:18]1[C:2]([C:24]#[C:23][C:22]([CH2:26][F:27])([OH:25])[CH2:21][F:20])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC(O)(CF)CF
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC(O)(CF)CF)cc1-2
Yield: 32 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol to give the titled compound as an off-white solid (73 mg, 32%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH:17]=[CH2:18].C(Cl)(Cl)Cl>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: C=CCn1c2ccccc2c2ccccc21
Yield: 100 %

Procedure:
Carbazole (10.1 g, 0.057 mol) and potassium hydroxide (88% wt pellets, crushed, 7.1 g, 0.11 mol) were stirred in 100 mL DMSO at 50° C. for 30 min before dropwise addition of allyl bromide (14.7 g, 0.118 mol). After 15 min the reaction mixture was poured into a 500 mL separatory funnel containing 100 mL chloroform and washed 5 times with 200 mL water to give, after solvent evaporation at 60° C. under reduced pressure, compound 15 in >99% purity as a dark brown, viscous syrup which solidified upon cooling (11.9 g, 0.057 mol, 100% yield). 1H NMR (300 MHz, CDCl3): δ=8.14-8.06 (m, 2 carbazole H), 7.49-7.32 (m, 4 carbazole H), 7.28-7.19 (m, 2 carbazole H), 6.04-5.90 (m, CH═CH2), 5.19-5.10 (m, Z-HCH═CH), 5.07-4.97 (m, E-HCH═CH), 4.92-4.85 (m, NCH2). 13C NMR (300 MHz, CDCl3): δ=140.34, 132.27, 125.67, 122.90, 120.33, 119.00, 116.74, 108.74, 45.21.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH2:24][Br:25])[C@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(O)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:25][CH2:24][CH2:23][CH2:22][N:10]1[C:9]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:5](=[O:6])[C:8]=2[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11]1=[O:21]
Reactant: O=C(O)[C@H]1c2ccc([N+](=O)[O-])cc2C(=O)N(CCCBr)[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1c2ccccc2-c2c1c1ccc([N+](=O)[O-])cc1c(=O)n2CCCBr
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Thionyl chloride (5 mL) was added to a solution of cis-4-carboxy-3,4-dihydro-N-(3-bromopropyl)-3-phenyl-7-nitro-1(2 H)isoquinolorie (8b) (1.000 g, 2.308 mmol) in benzene (50 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (30 mL), chilled in an ice bath, and aluminum chloride (0.616 g, 4.616 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1 h. Ice water (100 mL) was added and the solution was extracted with CHCl3 (3×100 mL). The combined organic layer was washed with sat NaHCO3 (3×50 mL), sat NaCl (50 mL) and dried over sodium sulfate. The solution was concentrated, hexanes (900 mL) were added, and liquid was decanted. The obtained solid was washed with hexanes (100 mL) and the liquid was again decanted. The crude solid was purified by flash column chromatography (SiO2), eluting with chloroform, to provide an orange solid (0.432 g, 45%): mp 258-260 (dec). IR (film) 1672, 1612, 1560, 1503, 1428, and 1337 cm−1; 1H NMR (CDCl3) δ 9.20 (d, J=2.4 Hz, 1 H), 8.89 (d, J=8.9 Hz, 1 H), 8.52 (dd, J=9.0 Hz and 2.4 Hz, 1 H), 7.92 (m, 1 H), 7.75 (m, 1 H), 7.57-7.52 (m, 2 H), 4.76 (m, 2 H), 3.70 (t, J=6.2 Hz, 2 H), 2.54 (m, 2 H); CIMS m/z (rel intensity) 413/415 (MH+, 100/82). Anal. (C19H13BrN2O4) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:17][CH2:16]1)=O)(C)(C)C>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccccc1OC1CCNCC1

Procedure:
Trifluoroacetic acid (4 mL) was added to crude carbamate 10.6 (1.030 g). After 20 min at rt most of the volatiles were removed in vacuo and 1 M HCl (10 mL) was added, whereupon an oil separated. This was washed with DCM (3×3 mL). The aqueous portion was basified to pH>12 with 5 M NaOH, extracted with DCM (3×4 mL), dried (MgSO4), filtered and concentrated to an oil (10 mg). The initial DCM washing was dried (MgSO4), filtered and concentrated to a pale yellow oil (1.26 g), whose 1H NMR was consistent with being the piperidinium trifluoroacetate. This material, plus the initial collected free base (10 mg) was dissolved in ether (30 mL) and washed with 5 M NaOH (10 mL), 1 M NaOH (2×10 mfL), water (10 mL) and saturated NaCl (2×10 mL), then dried (MgSO4) and filtered. HCl—saturated ether (35 mL) was added and the turbid solution was extracted with 1 M HCl (3×10 mL). The acidic portion was basified with 5 M NaOH, extracted with DCM (3×8 mL) and the organic portion dried (MgSO4), filtered and concentrated to a pale yellow oil (457 mg; 62% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester). LC (method B) tR=8.2 min; 1H NMR (200 MHz, CDCl3) δ 7.37 (dd, J=1.6, 8.0 Hz, 1H), 7.19 (ddd, J=1.5, 7.3, 8.6 Hz, 1H), 7.0-6.8 (m, 2H), 4.42 (tt, J=3.9, 3.9 Hz, 1H), 3.18 (ddd, J=4.0, 6.3, 12.0 Hz, 2H), 2.73 (ddd, J=3.7, 8.6, 12.3 Hz, 2H), 2.00 (m, 2H), 1.77 (m, 2H); ESIMS (free base) 212.0/213.9 (100/37) [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[NH:5]C(=O)C)[CH3:2].[OH-].[Na+].NC1C=CC=CC=1>C(O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1cc(Cl)ccc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Nc1ccccc1
Product: CCc1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
2'-Ethyl-4'-chloroacetanilide (31 grams) was heated to reflux in a mixture containing 80 milliliters of ethanol and 55 milliliters of concentrated HCL for about 2.5 hours. After cooling to room temperature, the mixture was basified to a pH of about 8 by an aqueous NaOH solution (20 percent). An oily aniline layer was observed. The mixture was transferred to a separatory funnel and was extracted with ether (3 times 75 milliliters). The ethereal extracts were combined and dried over MgSO4. After filtration, ether was removed under reduced pressure. 2-Ethyl-4-chloroaniline was purified and isolated by a reduced pressure distillation, yield 14.2 grams (58 percent).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>C1(C)C=CC=CC=1>[CH3:10][C:9](=[N:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C)cc1)c1ccccc1

Procedure:
p-Toluidine (0.20 mole), acetophenone (0.20 mole), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) were azeotropically refluxed in toluene (150 cc). The required amount of water had been removed after 3 hours. The solvent was removed on the rotary, and the residue was distilled under reduced pressure to give N-(α-methylbenzylidene)-p-toluidine. b.p. 129°-37° C./0.05 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:22][CH3:23])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]([CH3:52])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:43]2[C:38]([CH:39]=[N:40][C:41](OS(C(F)(F)F)(=O)=O)=[N:42]2)=[CH:37][CH:36]=1)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>COCC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:41]3[N:40]=[CH:39][C:38]4=[CH:37][CH:36]=[C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH3:52])[N:43]4[N:42]=3)=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 100 °C

Procedure:
4-(4-Amino-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 1.0 equiv), trifluoromethanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (70 mg, 1.0 equiv) and N,N-diisopropylethylamine (54 1, 2.0 equiv) were dissolved in 1-methoxy-2-propanol, and heated to 100° C. overnight. Concentrated, and purified by preparative TLC, 60% EtOAc/hexane containing 1% triethylamine. Obtained 4-hydroxy-4-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a brown solid, 43 mg. mp 111-112° C. LCMS (E/I+) 623 (M+H). NMR 1H (CDCl3) 8.71 (s, 1H), 8.12 (d, J=4.74 Hz, 1H), 7.90-7.96 (m, 1H), 7.46-7.58 (m, 3H), 7.00-7.05 (m, 2H), 6.79-6.89 (m, 2H), 3.96-4.11 (m, 2H), 3.89 (s, 3H), 3.17-3.29 (m, 2H), 3.12 (s, 3H), 2.66 (s, 3H), 1.85-2.01 (m, 2H), 1.58-1.67 (m, 2H), 1.60 (s, 1H), 1.50 (s, 9H).