Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.C(OC1C=CC=CC=1NC=[C:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][C:24](S(N)(=O)=O)=[CH:23][CH:22]=2)[N:17]=[C:16]1[CH3:31])C.C[N:37](C1C=CC=CN=1)C>N1C=CC=CC=1>[NH2:37][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[C:19](=[O:20])[CH2:15][C:16]([CH3:31])=[N:17]2)=[CH:22][CH:23]=1
Reactant: CN(C)c1ccccn1
Reactant: CCOc1ccccc1NC=C1C(=O)N(c2ccc(S(N)(=O)=O)cc2)N=C1C
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reaction time: 10 h

Procedure:
0.17 ml of acetic anhydride is added dropwise to a solution of 1.0 g of 4-(4-(2-ethoxyanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzenesulfonamide and 0.9 g of dimethylaminopyridine in 30 ml of pyridine while cooling in ice, and the mixture is then stirred for 10 hours. The residue obtained after concentration in vacuo is mixed with dilute hydrochloric acid, and the crystals which have separated out are filtered off with suction and triturated with ethanol.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[O:41][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:44]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:42]4[O:41][C:40]([CH3:39])=[N:44][CH:43]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)o1
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.1 mmol) was treated with 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (52 mg, 0.25 mmol), tetrakistriphenylphosphine palladium (35 mg, 0.03 mmol) and aqueous solution of sodium carbonate (2M, 125 μl, 0.25 mmol) in DMF (1.5 ml). The reaction mixture was submitted at vacuum-argon cycles and stirred at 100° C. for 2 h. The reaction mixture was allowed to cool down to room temperature and poured over ice, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by normal phase using SP1® Purification System (0% to 100%, hexane-diethyl ether) to obtain 31 mg (52% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C(C)=CC=CC=1C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 50 °C

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (example 59)(22 mg, 0.063 mmol), acetic anhydride (9 mg, 0.082 mmol), 2,6-lutidine (11 mg, 0.10 mmol), DMAP (10 mg, 0.082 mmol) and DMF (0.5 mL) was heated at 50° C. for 2 hrs. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-100% CH3CN in 0.1% TFA/H2O over 30 mins to give 15 mg (60%) the title cpd. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.80 (s, 1H), 7.68 (m, 1H), 7.46 (m, 4H), 7.30 (m, 2H), 6.96 (m, 2H), 2.04 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H14ClN3O3 379.1, found 380.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=O.CC1(C)CCCC(C)C1CC[CH2:22][C:23]([OH:25])=[O:24].CC1(C)C(C)CCC1CCCC(O)=O>>[CH3:9][C:4]1([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]1[CH2:10][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: CC1CCCC(C)(C)C1CCCC(=O)O
Agent: CC1CCC(CCCC(=O)O)C1(C)C
Product: CC1CCCC(C)(C)C1CCC(=O)O

Procedure:
3-(2,2,6-trimethylcyclohexyl)propanoic acid was synthesized in three steps starting from 2,6,6-trimethylcyclohex-1-enecarbaldehyde, analogous to the 3-step procedure described for 4-(2,2,6-trimethylcyclohexyl)butanoic acid and 4-(2,2,3-trimethylcyclopentyl)butanoic acid herein-above, as indicated below.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na]>C(OC(=O)OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccccc2)cc1
Temperature: 120 °C
Yield: 152.8 %

Procedure:
A solution of ethyl (4′-biphenyl)acetate (7.1 g) in 60 ml of diethylcarbonate, kept under nitrogen atmosphere, is added portionwise with sodium (0.734 g), then it is heated at 120° C. for 3 hours. The solvent is evaporated off and the residue is dissolved in 65 ml of cold water and acidified with acetic acid until pH=5-6 is reached. The aqueous phase is then extracted three times with diethyl ether and the pooled organic extracts are dried over sodium sulfate and concentrated to dryness. The residue is purified by silica gel chromatography (eluent: petroleum ether/diethyl ether 9.4:0.6) to give 7.05 g of the product. m.p. 51-53° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH:5]=1.C([Mg]Br)C.C(O[C@H:22]1[NH:25][C:24](=[O:26])[C@@H:23]1[C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])(=O)C.Cl>O1CCCC1.C(OCCCC)(=O)C>[Si:30]([O:29][C@@H:27]([C@@H:23]1[C@@H:22]([C@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C:4]2=[O:3])[NH:25][C:24]1=[O:26])[CH3:28])([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CO[C@H]1CCCC=C1O[Si](C)(C)C
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCOC(C)=O
Product: CO[C@H]1CCC[C@H]([C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To a solution of 1-trimethylsilyloxy-6-(S)-methoxy-1-cyclohexene (800 mg, 4 mmol) in tetrahydrofuran (5 ml), a tetrahydrofuran solution containing 1 mol/liter of ethylmagnesium bromide was added and stirred at room temperature for 3 days. This mixture was then cooled to 0° C., and a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl)-2-azetidinone (861 mg, 3 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture and stirred at 0° C. for 1 hour. The resultant mixture was subjected to addition of 2N hydrochloric acid and extraction with butyl acetate. The organic phase was washed with a saturated sodium hydrogencarbonate solution and water, and concentrated under a reduced pressure to obtain a crude product of (3S,4R)-3-[(R)-1-((tert-butyldimethylsilyl)oxy)ethyl]-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]azetidin-2-one. The crude product contained 170 mg of the objective β-isomer. The yield was 16%, and the β:α ratio was 90:10.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[OH:2][CH2:1][CH2:3][N:4]=[C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=2[CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2
Reactant: NCCO
Reactant: O=C1c2ccccc2CCc2ccccc21
Product: OCCN=C1c2ccccc2CCc2ccccc21

Procedure:
600 ml. of ethanolamine are added to 208 g. of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one. The mixture is heated under reflux conditions in an inert gas atmosphere for 16 hours. The refluxing ethanolamine is recycled into the reaction vessel through a Soxhlet attachment filled with 2 × 130 g. of 4A molecular sieve (bead form, 2 mm; Merck). The resulting mixture is then evaporated. The residue is dissolved in ether. The ether solution is washed with water and extracted with ice-cold 1N nitric acid. The acid extracts are washed with ether, adjusted to a pH value of 10-12 by addition of cold concentrated sodium hydroxide solution and subsequently extracted with methylene chloride. The methylene chloride extract is washed with water, dried over calcium chloride and evaporated under reduced pressure. The N-(2-hydroxy-ethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine which is obtained melts at 93°-94° C. after recrystallization from acetone/petroleum ether: 3:5.
Reaction SMILES: [ClH:1].C(N(CCC(OCC)=O)C(C1C=CC2N(C)C(CSC3C=CC(C(=N)N)=CC=3)=NC=2C=1)=[O:7])CC.OO.Cl.[CH2:39]([N:42]([CH2:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[C:43]([C:45]1[CH:66]=[CH:65][C:48]2[N:49]([CH3:64])[C:50]([CH2:52][S:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61](=[NH:63])[NH2:62])=[CH:57][CH:56]=3)=[O:54])=[N:51][C:47]=2[CH:46]=1)=[O:44])[CH2:40][CH3:41].C(OCC)(=O)C.C(O)C>C(O)=O>[ClH:1].[CH2:39]([N:42]([CH2:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[C:43]([C:45]1[CH:66]=[CH:65][C:48]2[N:49]([CH3:64])[C:50]([CH2:52][S:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61](=[NH:62])[NH2:63])=[CH:57][CH:56]=3)(=[O:7])=[O:54])=[N:51][C:47]=2[CH:46]=1)=[O:44])[CH2:40][CH3:41]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CS(=O)c1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: OO
Solvent: O=CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CS(=O)(=O)c1ccc(C(=N)N)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 0.40 g (0.70 mmol) of 1-methyl-2-[(4-amidinophenyl)thiomethyl]benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride in 10 mL of formic acid was mixed with 2 mL of 30% hydrogen peroxide solution and the mixture was stirred for 16 hours at room temperature. Then the solvent was distilled off in vacuo, whereupon the desired compound was obtained as a beige solid (contaminated with some 1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride). Yield: 95% of theory, C25H31N6O5S (513.62); Rf value: 0.50 (silica gel; ethyl acetate/ethanol/1N hydrochloric acid=50:45:5); EKA mass spectrum: (M+H)+=514.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)OCC
Yield: 55.9 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (25.6 g) and 4-methoxybenzyl chloride (25.0 g). This was purified by silica gel column chromatography to give the title compound (25.0 g) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34]C)=[O:33].[OH-].[Li+].CO>O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
A solution of (R)-methyl 2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (105 mg, 0.189 mmol, 1 equiv) and lithium hydroxide (15.9 mg, 0.38 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at ambient temperature for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (21 mg, 20%); 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H); 2.79-2.85 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 Hz); 4.11 (d, 1H, J=4.8 Hz); 4.91 (d, 1H, J=4.8 Hz); 5.71 (s, 1H); 6.76-6.82 (m, 3H); 6.97-6.98 (m, 3H); 7.17-7.23 (m, 3H); 7.35-7.43 (m, 5H); 10.83 (s, 1H); 12.5 (bs, 1H); MS for C31H33ClN5O4 540.01 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1cccc(Cl)c1
Yield: 97.6 %

Procedure:
Step AP (1): 2-(3-Chlorophenyl)acetic acid (5 g, 29.3 mmol) was deprotonated with NaHMDS (2.0 M in THF, 29.3 mL, 58.6 mmol) and reacted with 1-chloro-4-iodobutane (3.59 mL, 29.3 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3-chlorophenyl)hexanoic acid (7.47 g, 98% yield). LC-MS (M−H)− 259.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[OH-].[NH4+]>[Ni].C(O)C>[NH2:2][CH2:1][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: N#Cc1ccc2ccccc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc2ccccc2c1
Reaction time: 108 h

Procedure:
A mixture of 10.0 g (65.3 mmole) 2-cyanonaphthalene, 2.0 g Raney Nickel, 100 ml ethanol and 9 ml concentrated ammonium hydroxide was hydrogenated at 36 psi (2.53 kg/cm2) for 4.5 days. The mixture was filtered and the filtrate concentrated in vacuo to an oil. The oil was distilled in vacuo to obtain the desired amine as a colorless liquid which solidified on standing. Yield 2.02 g. TLC on silica gel plates showed one spot at Rf 0.1 upon development with 19:1 chloroform/methanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)C=C.[CH2:13]1[C:22]2C(=CC=CC=2)CC[CH2:14]1.B(F)(F)F.CCOCC>>[CH2:22]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][CH2:5][CH2:6]2)[CH:13]=[CH2:14]
Reactant: C=CCN1CCc2ccccc21
Reactant: c1ccc2c(c1)CCCC2
Agent: FB(F)F
Solvent: CCOCC
Product: C=CCc1cccc2c1NCC2
Temperature: 200 °C
Yield: 77 %

Procedure:
A mixture of 2,3-dihydro-1-(2-propenyl)-1H-indole (1.59 g), tetralin (25 ml) and borontrifluoride etherate (1.3 ml) was heated at 200° C. for 1.5 hours. The reaction mixture was cooled to room temperature then quenched with 10% sodium carbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and evaporated. The residue was chromatographed over silica (ethyl acetate-hexane 15:85) affording 1.23 g of the desired product (77% yield).
Reaction SMILES: [N+:1]([CH:4]1[C:13]23S[C:6]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:7](=[O:18])[N:8]2[CH2:9][CH2:10][C:11]2[CH:17]=[CH:16][S:15][C:12]=23)[CH2:5]1)([O-:3])=[O:2].C[O-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7](=[O:18])[N:8]2[C:13]=1[C:12]1[S:15][CH:16]=[CH:17][C:11]=1[CH2:10][CH2:9]2)([O-:3])=[O:2]
Reactant: O=C1N2CCc3ccsc3C23SC1(c1ccccc1)CC3[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1c(-c2ccccc2)cc([N+](=O)[O-])c2n1CCc1ccsc1-2

Procedure:
1.58 g of 4,5,9,10-tetrahydro-10-nitro-8-phenyl-8,10a-epithio-10aH-thieno[2,3-a]quinolizin-7(8H)-one were heated slowly together with 2 equivalents of sodium methylate in 30 ml of methanol. After the reaction ceases, the mixture was heated under reflux for an additional 2 hours, whereupon the solvent was removed by distillation and the residue was chromatographed on silica gel with toluene/acetone (9:1). There was obtained 4,5-dihydro-10-nitro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 186°-189° (from acetonitrile) and in a later fraction 10-amino-4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 180.5°-181.5° (from toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].Cl.CN.Cl.[CH2:16]([N:18]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:18][CH3:16])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(F)c(Cl)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a suspension of 3-chloro-4-fluorobenzoic acid (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23° C. The reaction was stirred at 23° C. for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23° C. affording a suspension. The suspension was filtered, washed with H2O (3×100 mL), and the resulting solid was dried in vacuo at 30° C. to provide 3-chloro-4-fluoro-N-methylbenzamide (14.24 g, 76 mmol, 53.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3H) 7.53 (t, J=8.97 Hz, 1H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1H) 8.04 (dd, J=7.20, 2.15 Hz, 1H) 8.51-8.65 (m, 1H). ESI-MS: m/z 188.0 (M+H)+. Mp=108.3-110.0° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:36])[CH:3]([C:18]1[C:19]([CH3:35])=[C:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1.CC1C=CC(C)=CC=1>O1CCOCC1.[Pd].CCOC(C)=O>[CH2:27]([O:26][C:25]([NH:24][C:20]1[C:19]([CH3:35])=[C:18]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][C:2]=2[CH3:36])[CH:23]=[CH:22][CH:21]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)N)c[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)c(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OCCOC)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a homogeneous, colorless solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate (1.3975 g, 2.87 mmol) in dioxane (Volume: 143 ml) under nitrogen were added 50% ethyl 2-oxoacetate/toluene (1.136 ml, 5.73 mmol) and 4 N hydrochloric acid/1,4-dioxane (1.433 ml, 5.73 mmol). After stirring overnight, the reaction was concentrated in vacuo, dissolved in EtOAc (75 mL) and saturated aqueous NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×75 mL). the organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give crude cyclized product as a burgundy oil which was used in the next step. p-Xylene (Volume: 82 ml) and 10% palladium on carbon (0.916 g, 0.861 mmol) were added, and the reaction was heated at 120° C. After 3 h, the reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, dissolved in EtOAc (125 mL) and washed with water (25 mL). The layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 80 g column eluting with 20-75% EtOAc/hexane. Appropriate fractions were collected and concentrated in vacuo to give ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (0.6232 g, 1.098 mmol, 38.3% yield) as a tan solid, LC/MS (M+H)=568.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]4[S:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)=[CH:15][CH:16]=3)[C:11]([CH2:29][C:30](O)=[O:31])=[C:10]2[CH3:33])=[CH:4][CH:3]=1.ClC(OCC)=O.[OH-].[NH4+:41]>O1CCCC1.C(N(CC)CC)C.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[CH2:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([CH3:33])=[C:11]2[CH2:29][C:30]([NH2:41])=[O:31]
Reactant: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture containing the compound of Example 37(0.5 g, 1.05 mmol) in tetrahydrofuran (30 mL) and triethylamine (0.6 mL) at -10° C., is added slowly with stirring a solution of ethyl chloroformate (0.14 g, 1.29 mmol) in tetrahydrofuran (10 mL). After 30 minutes, 30% ammonium hydroxide (0.6 mL) is added and the mixture is stirred for 18 hours at 23° C. The mixture is diluted with water (100 mL) and is extracted with ethyl acetate (3×100 mL). The combined extract is washed with 2N HCl (200 mL) and brine (200 mL), dried over MgSO4 and concentrated to give crude product (0.55 g). Crystallization from acetonitrile gives pure title compound in 90% yield as a white solid, m.p. 169°-170° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[CH:9][C:10]2[NH:14][CH2:13][CH2:12][N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=NCCN1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1)C1=NCCN1

Procedure:
A solution of 5.3 g (50 mmol) of benzaldehyde and 4.2 g (50 mmol) of 2-methyl-4,5-dihydro-1H imidazole in 50 ml toluene was refluxed in a Dean-Stark apparatus. Within 8 h 0.9 ml of water had been separated and the reaction was almost complete as detected by TLC. After cooling the crystalline precipitate was filtered off, treated with cold tert.-butylmethylether, and dried in vacuo.