Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>ClCCl.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: O
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoroaniline (15 g, 0.135 mol) in dichloromethane (100 mL) was added 3-chloropropanoyl chloride (15.168 mL, 0.135 mol) under cooling condition (0° C.) with constant stirring. Reaction mass was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 201.9.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([Li])[CH2:8][CH2:7]3.[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>C1COCC1>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1CCc2cc3c(cc21)C(c1ccccc1)=C(C)C3
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Temperature: 22.5 °C
Yield: 96.1 %

Procedure:
(6-Methyl-7-phenyl-1,2,3,5-tetrahydro-s-indacenyl) lithium (17.8305 g, 0.07068 moles) 25 in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (21.3694 g, 0.1656 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at 20-25° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a viscous yellow oil (23.0231 g, 96.1 percent).
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[OH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22][N:32]5[CH2:33][CH2:34][C@H:30]([OH:29])[CH2:31]5)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2cc3cc(-c4c5c(nc6ccnn46)CCC5)ccc3o2)C1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 3-(S)-hydroxypyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give 1-{2-[5-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethyl}-pyrrol idin-3-(S)-ol.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4][C:3]1([CH3:20])[CH3:19].O1CCOCC1.[OH-].[Na+]>O>[CH3:19][C:3]1([CH3:20])[CH:2]2[O:12][CH:11]2[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4]1
Reactant: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C(O)C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C2OC21
Temperature: 20 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
A mixture containing 2.9 g of 3-bromo-2,2-dimethyl-4-hydroxy-6-trifluoroacetylchromane, prepared in the previous step, 25 ml of dioxane, 0.5 g of sodium hydroxide pellets and 5 ml of water is stirred at 20° C. for 20 hours. After concentration under vacuum at 40° C., the residue is treated 4 times with 100 ml of ethyl ether and the extracts are then dried and concentrated under vacuum to give 2 g of a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(O)C>[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][N:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:1])=[CH:17][CH:16]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CC(=O)c1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1

Procedure:
N-Methylbenzylamine (22.43 g), 4-methanesulphonamidophenacyl bromide (50 g) (see J. Med. Chem. 1966, 9, 88) and triethylamine (17 g) in ethanol (500 ml) were stirred at room temperature for 18 hours. The solvent was removed, the residue was taken up in dilute hydrochloric acid, washed with ethyl acetate and the organic layer was discarded. The aqueous layer was neutralised with sodium bicarbonate and then extracted three times with ethyl acetate. The combined organic extracts were evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)] eluting with hexane containing ethyl acetate (0% up to 100%). The title compound was obtained as an oil by collection and evaporation of appropriate fractions. The oil solidified when triturated with ether, yield of the title compound 32 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:6]=1[O:13]C.[BrH:15]>>[BrH:15].[NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:13]
Reactant: COc1ccc(OC)c(CCCN)c1
Agent: Br
Product: NCCCc1cc(O)ccc1O
Yield: 69.3 %

Procedure:
100 g of γ-aminopropyl-2,5-dimethoxybenzene was heated at an oil bathtemperature of 180° C in 830 ml of 48% hydrobromic acid while blowing therein nitrogen gas. After the reaction, the reaction mixture wascooled, and the precipitated crystals were filtered out and dried to obtain88 g of the end product having a melting point of 130° ~ 131° C (yield 69.3%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:13][C:14]([F:22])([F:23])[CH2:15][CH2:16][C:17]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([C:20]#[N:21])[C:18]#[N:19]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 65.8 %

Procedure:
Using 0.15 g of (4-vinylbenzyl)chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil) and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 27, there was obtained 0.18 g of 2-(3,3,3-trifluoropropyl)-2-(4-vinylbenzyl)malononitrile (the present compound (27)).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].CO.Cl.[CH:21]([OH:24])(C)C>CCO>[ClH:13].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:24][CH3:21])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(C)O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2 atmosphere, 11 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0° C. After 20 minutes, the cooling bath is removed and the reaction mixture is stirred at ambient temperature. After the reaction is completed, the mixture is evaporated to dryness in vacuo. The residue is stirred in 75 ml of H2O and the mixture is made alkaline with 6N NaOH solution and extracted with CH2Cl2 (3×50 ml). The organic phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtOH and acidified with HCl/isopropyl alcohol solution to pH 2. The solution is evaporated to dryness and the residue is stirred in 75 ml of ethyl acetate. After cooling, this affords a pale yellow solid which is collected to give 6.97 g of the title compound, m.p. 195°-198° C. dec.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:32])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][NH:15]2)[CH:3]=1.CO.[O:35]1[CH2:40][CH2:39]OCC1>>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:32])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:40]([CH:39]2[CH2:11][NH:2][CH2:3][CH2:4][NH:12]2)=[O:35])[CH:3]=1
Reactant: C1COCCO1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2cnc3ccccc3c2)N(C(=O)C2CNCCN2)C1)[C@H](O)CCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5 mL) was added to 1,4-di-(N-tert-butoxycarbonyl)piperazin-2-ylcarbonyl)-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (C, 76 mg) at 0° C., and methanol (2 mL) was added to dissolve insoluble materials. After stirring for 1.5 hr, the reaction mixture was evaporated and coevaporated three times with 1,4-dioxane and ether in vacuo to give pale yellow solids. The solids were washed with ether to afford the title compound (64 mg) as a colorless solid: 1H NMR (400 MHz, D2O) δ 1.92-2.05 (m, 2H), 2.34-2.48 (m, 1H), 2.67(t, 2H), 3.24-4.89 (m, 13H), 7.15-7.32 (m, 5H), 7.83 (t, 1H), 7.96 (t, 1H), 8.09-8.16 (m, 2H), 8.94 (d, 1H), and 9.27 (d, 1H); mass spectrum (FAB+) m/e 531 (M+1); Anal. Calcd. for C29H34N6O4.3HCl.3H2O: C, 50.06; H, 6.26; N, 12.08. Found: C, 50.56; H, 6.34; N, 1.48.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:16])[CH:10]=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.[H-].[Na+]>>[NH:21]1[CH2:26][CH2:25][CH:24]([O:27][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:16])[CH:10]=2)[CH2:23][CH2:22]1
Reactant: OC1CCNCC1
Reactant: Nc1cc(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [H-]
Agent: [Na+]
Product: Nc1cc(OC2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
1-Cyclopropyl-5-amino-7,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 4-piperidinol and sodium hydride were reacted and treated in a similar manner to Example 9, whereby the title compound was obtained as colorless powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([NH2:15])=[N:13][N:14]=3)[N:11]=2)[CH2:3][CH2:2]1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:23]([O:32][CH3:33])=[C:22]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:21]=1)=[O:19].[ClH:38]>CN(C=O)C>[ClH:38].[C:34]([C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH2:17][N:13]2[C:12](=[NH:15])[N:10]3[N:11]=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[CH:8][C:9]3=[N:14]2)[CH:25]=[C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:23]=1[O:32][CH3:33])([CH3:37])([CH3:35])[CH3:36]
Reactant: Nc1nnc2ccc(OCC3CC3)nn12
Reactant: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1c(N2CCOCC2)cc(C(=O)Cn2nc3ccc(OCC4CC4)nn3c2=N)cc1C(C)(C)C

Procedure:
6-Cyclopropylmethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.009; 350 mg) was initially charged in DMF (5 ml) at RT while stirring, and 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)ethanone (O1.003; 631 mg) predissolved in DMF (5 ml) was added dropwise. The reaction mixture was stirred at RT for 14 h. Then the solvent was removed under reduced pressure and the residue was purified using silica gel (40 g cartridge, dichloromethane/ethanol gradient of 0-40% in 60 min). The product was taken up with a little acetonitrile, diluted with water and, after addition of 2 eq. of HCl, freeze-dried. 500 mg of the title compound were obtained. LC-MS rt: 1.37 min [M+H]+: 495.2 (met. a)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]=[C:20]=[S:21]>>[CH3:18][NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[S:21]
Reactant: CN=C=S
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CNC(=S)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 85.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.56 mg (0.098 mMol) methyl isothiocyanate, 17.0 mg (86%) of the title compound were recovered.
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:32]([C:34]1[C:35](O)=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)#[N:33].P(Cl)(Cl)([Cl:52])=O>C(O)C>[Cl:52][C:35]1[C:34]([C:32]#[N:33])=[CH:39][N:38]=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[N:36]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-propylbenzamidine hydrochloride with α-ethoxymethylene- α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-propylphenyl)-pyrimidine (melting point 246.0°-247.6° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-propylphenyl)-pyrimidine having a melting point of 109.4°-109.7° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[OH:11][C@:12]1([CH3:19])[C@H:16]([CH3:17])[NH:15][C:14](=[O:18])[CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:15]2[C:14](=[O:18])[CH2:13][C@@:12]([OH:11])([CH3:19])[C@@H:16]2[CH3:17])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C[C@]1(C)O

Procedure:
Using 4-bromo-2-chlorobenzonitrile (615 mg), (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one (423 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (241 mg), tris(dibenzylideneacetone)dipalladium(0) (125 mg) and cesium carbonate (1.31 g), and in the same manner as in Reference Example 18, the title compound was obtained as a colorless solid (yield: 431 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccccc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccccc3)ccc2CCC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.1 %

Procedure:
To methyl 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.28 g, 7.39 mmol) suspended in methanol (25 ml) was added a 1N aqueous solution of sodium hydroxide (23 ml), and the resulting mixture was stirred at room temperature for 13 hours. In order to complete the reaction, tetrahydrofuran (25 ml) was added, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (23 ml) at room temperature, was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2.09 g, 7.10 mmol, 96%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CC#N>[CH2:1]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CC#N
Product: c1ccc(CNCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To carry out the oxidative condensation, benzylamine (0.5 mmol) was heated with catalyst Pd@ba-GO (10 mg) and solvent CH3CN (0.2 mL) at 90° C. in a flask open to air for 6 hours, and then stirred also at 90° C. under H2 gas (1 atm) for 6 hours to obtain dibenzylamine. An unexpectedly high yield of 91% was achieved.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[ClH:12].[CH2:13]=O>O>[ClH:12].[ClH:12].[N:8]1[C:4]2[CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH:1][CH2:13][C:5]=2[NH:6][CH:7]=1
Reactant: C=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1Cc2nc[nH]c2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
L-Histidine (204.8 g, 1.32 mol) was added to water (1.2 L) and cooled in an ice/water bath. Concentrated hydrochloric acid (116.0 mL, 1.39 mol, 1.05 mol eq.) was added slowly. Formaldehyde (37 wt/wt % in water, 112.5 g, 1.39 mol, 1.05 mol eq.) was added in one portion. The reaction mixture was stirred for 30 min upon cooling with an ice/water bath, and then refluxed for 75 min. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was suspended in isopropanol (2 L) and HCl (400 mL of a 4 M solution in dioxane) for 30 min. The white solid was filtered and washed with ether. After drying in a vacuum oven (40° C.), the title product was obtained. (313.0 g, 99% yield, 95% pure). 1H NMR (DMSO-d6): 8 ppm 3.05-3.33 (m, 2H), 4.30 (s, 2H), 4.54 (m, 1H), 9.00 (s, 1H), 12.60 (br s, 3H). LCMS: Rt=0.59 min, and M+1=168.1 m/z (M+1 of free base).
Reaction SMILES: [Na].Cl[C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[CH3:23][OH:24]>>[CH3:23][O:24][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Reactant: CO
Agent: [Na]
Solvent: Cc1ccccc1
Product: COc1ccc2cccnc2c1[N+](=O)[O-]

Procedure:
To a freshly prepared solution of sodium (16.5 g, 0.720 mol) in methanol (750 mL) was added 7-chloro-8-nitroquinoline (18.72 g, 0.090 mol) [E. Fourneau, M. and Mme. Trefouel, and A. Wancolle, Bull. Soc. Chim. Fr., 47, 738(1930); A. K. Sen, N. K. Ray, V. P. Basu, J. Sci. Ind. Res., 11B, 322(1952) (C.A. 47, 4339e)]. This mixture was refluxed for 3 hr, cooled, then filtered to collect the precipitated solid. This solid was slurried in water, collected on a filter and dried; yield, after recrystalllization from toluene, 16.12 g (88%); mp 178°-178.5°: Anal. Calcd for C10H8N2O3 : C, 58.82; H, 3.95; N, 13.72. Found: C, 58.66; H, 3.87; N, 13.69.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:16]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=O)=[CH:27]3)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:33][C:28]1[NH:29][C:30]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:32][CH:31]=2)(=[O:5])=[O:4]
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[C:9](OCC)=[O:10]>CCOCC>[CH3:7][C:8]([CH3:18])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:9][OH:10]
Reactant: C=CCCC(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC(C)(C)CO
Temperature: 22 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
To a stirred solution of 1M LAH in ether (142.14 mL, 142.14 mmol), at 0° C. and under nitrogen, was added dropwise ethyl 2,2-dimethylhex-5-enoate (11.00 g, 64.61 mmol) dissolved in 100 mL anhydrous ether over 1 hour. This reaction solution was stirred at 22° C. for 20 hours, then quenched with water (3 mL), 1M NaOH (11 mL) and water (9 mL), dried over Na2SO4, filtered and concentrated to give the title product (7.22 g, 87.09%). 1H NMR (500 MHz, CDCl3) δ 5.85-5.77 (m, 1 H); 5.01 (d, 1 H); 4.93 (d, 1 H); 3.33 (d, 2 H); 2.03 (m, 2 H); 1.34 (m, 2 H); 0.89 (m, 6 H) ppm.
Reaction SMILES: [C:1]([C:9]1[N:10]([N:14]2C(=O)C3=CC=CC=C3C2=O)[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN>C(O)C.O>[NH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CCO
Product: Nn1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a suspension of 2-benzoyl-1-phthalimidopyrrole (35 g, 0.11 mole) in 350 ml ethanol was slowly added 45 ml methylamine (40% solution in water). After stirring two hours at ambient temperature, the mixture was diluted with 40 ml water and extracted with ether. The ether extract was washed with water and saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated to 28 g oil which upon trituration with hexanes gave 21 g (99%) solid, m.p. 65°-69°. 3.5 g of this material was purified by HPLC (silica gel, 4% ethyl acetate/dichloromethane) to give 2.8 g solid, which was recrystallized from hexanes to give 2.4 solid, m.p. 65°-67°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=2[N:12]=[C:11]1[C:29]([F:32])([F:31])[F:30].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[N:12]=[C:11]1[C:29]([F:30])([F:32])[F:31]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 4.57 %

Procedure:
A mixture of methyl 1-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate prepared as described in Example 51 (1.95 g, 3.99 mmol) and 2 M lithium hydroxide (0.096 g, 3.99 mmol) in Tetrahydrofuran (THF) was stirred at 50° C. for 3 h. The reaction was cooled to room temperature, the organic solvent was removed under reduced pressure and the aqueous residue was acidified (pH 4) by the addition of 1N HCl. A gummy precipitate formed. After standing at rt overnight, it turned into a solid. The precipitate was collected, washed with water and dried to give crude desired product (1.83 g, 3.86 mmol, 97% yield) as a gray solid. A portion of this material (148 mg) was purified by reverse phase-HPLC (15-95% AcCN in water plus 0.1% TFA). The fractions containing product were combined and the volume was reduced to about ⅓ of the original. The precipitate formed was collected, washed with water and dried in a vacuum oven to give desired product (88.3 mg, 0.182 mmol, 4.57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.64 (d, J=2.53 Hz, 1H), 7.61 (dd, J=8.08, 1.26 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.24 (t, J=8.08 Hz, 1H), 6.26 (dd, J=7.83, 1.26 Hz, 1H), 5.77 (s, 2H), 3.66-3.81 (m, 4H), 3.12-3.25 (m, 4H). MS(ES+) m/e 474 [M+H]+.