Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19])=[CH:28][CH:27]=1
Reactant: CNCCc1ccc(Cl)cc1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1-cyano-1,1-diphenylpropane (0.9 g-see Preparation 4), N-methyl-4-chlorophenethylamine (0.51 g, see CA 61:15224h), anhydrous potassium carbonate (0.83 g) and acetonitrile (40 ml) was heated under reflux for 24 hours then partitioned between dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 40%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.25 g.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To tert-butyl 4-(2-methyl-4-quinolyl)piperazine-1-carboxylate (4.382 g, 13.38 mmol) was added 40 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with 5% sodium bicarbonate solution and 3M NaOH was added until the aqueous phase remained basic. The phases were separated, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium carbonate solution, water, dried over magnesium sulfate and evaporated to dryness. 2.1 g of a solid were obtained (9.25 mmol, 69%). MS (APCI): m/z=227.8 [M+1]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]([N+:21]([O-])=O)[C:9]=1[NH2:24].O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]([NH2:21])[C:9]=1[NH2:24]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame dried 500 mL three-necked round bottom flask purged with N2 was charged with LAH (2.32 g, 58.0 mmol) and dry THF (60 mL). The resulting suspension was cooled to 0° C. and a suspension of t-butyl ester 1 (10.0 g, 29.0 mmol) in dry THF (60 mL) was slowly added while keeping the internal reaction temperature under 5° C. The reaction was stirred at 0° C. for 30 min then at rt for 30 min. After the reaction was judged complete, the mixture was treated with successive dropwise addition of water (2.3 mL), 10% NaOH (2.3 mL), and water (7.2 mL). The resulting suspension was filtered through Celite, washed with ethyl acetate and methanol, and the collected organics concentrated. The crude product was absorbed onto silica gel and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.5 Hz, 1H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.29 (d, J=2.75 Hz, 1H), 6.92 (d, J=9.35 Hz, 1H), 6.75 (m, 2H), 4.68 (s, 2H), 3.07 (d, J=5.23 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:12][C:5]1[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:3]([OH:13])[CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of 1.2 g of 2-amino-5-chloro-4-trifluoromethylphenol, 1.35 g of WSC, 0.67 g of isonicotinic acid and 10 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.01 g of N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[CH3:10][N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: N#Cc1cccnc1F
Reactant: CN1CCC(O)C1
Product: CN1CCC(Oc2ncccc2C#N)C1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 1-methyl-pyrrolidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 204 (M+1)+.
Reaction SMILES: CC(C)=O.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH2:27]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 85.7 %

Procedure:
To a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxylate (630.1 g, 2.84 mol) was added potassium carbonate powder (785 g, 5.68 mol) and benzyl bromide (405 ml, 3.41 mol). The resulting suspension was heated to reflux for 16 hr. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give solid material, which was re-dissolved in AcOEt, washed with water to remove residual salt, dried over MgSO4, filtered, concentrated to a small volume. Addition of hexanes caused precipitation of the title compound, which was collected by suction-filtration. The filtrate was triturated from dichloromethane-hexanes to give more precipitates. Finally the filtrate was concentrated and chromatographed on silica gel eluting with 20 to 80% dichloromethane/hexanes. Combination of all crops yielded the title compound 760.2 g as off-white solid (86%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>O1CCCC1.[Zn]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:16]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)CBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCOCC1
Yield: 69.3 %

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (5.5 g, 51.6 mmol), a zinc powder (4.05 g, 61.9 mmol) and a small amount of iodine in tetrahydrofuran (60 ml) was added dropwise ethyl bromoacetate (6.28 ml, 56.7 mmol) under a nitrogen atmosphere. After heating under reflux for 6 hrs., 10% sulfuric acid (50 ml) was carefully added under ice-cooling and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (6.73 g, 69%) as a colorless oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:28]2[C:19](=[CH:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=2)[CH:18]=[C:17]2[C:12]=1[C:13]1[CH:44]=[CH:43][C:42]3[C:29](=[CH:30][C:31]4[C:40]([CH:41]=3)=[CH:39][C:38]3[C:33](=[CH:34][C:35](Br)=[CH:36][CH:37]=3)[CH:32]=4)[C:14]=1[CH:15]=[CH:16]2>C1(C)C(C)=CC=CC=1>[C:1]1([C:11]2[C:28]3[C:19](=[CH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH:18]=[C:17]3[C:12]=2[C:13]2[CH:44]=[CH:43][C:42]4[C:29](=[CH:30][C:31]5[C:40]([CH:41]=4)=[CH:39][C:38]4[C:33](=[CH:34][C:35]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:36][CH:37]=4)[CH:32]=5)[C:14]=2[CH:15]=[CH:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cc3cc4ccc5c(ccc6cc7cc8ccccc8cc7c(Br)c65)c4cc3cc2c1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccc3cc4cc5ccc6c(ccc7cc8cc9ccccc9cc8c(-c8ccccc8)c76)c5cc4cc3c2)cc1

Procedure:
Naphthacenonaphthacene (Chemical Abstract Service (CAS) Registry Number 180-50-1) is dissolved in carbon tetrachloride. While the resultant mixture is cooled, 1 mol equivalent of bromine is added thereto. The mixture is reacted for 4 hours and brominated. Thereafter, the mixture is purified in accordance with a usual method, and 6,13-dibromonaphthacenonaphthacene is obtained. 2 mol equivalent of phenylboronic acid [Ph—B(OH)2] (where “Ph” represents a phenyl group) is refluxed and reacted for 12 hours with the 6,13-dibromonaphthacenonaphthacene obtained in this way, in a xylene/2M sodium carbonate aqueous solution, by using 0.01 mol equivalent of tetraquis(triphenylphosphine)palladium (0) [Pd(PPh3)4] (where “Ph” represents a phenyl group) as a catalyst. Thereafter, the resultant mixture is purified in accordance with a usual method, and the 6,13-diphenyl-naphthacenonaphthacene expressed by the following formula is synthesized. (Note that, in the formula, “Ph” represents a phenyl group.)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[CH:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[C:3]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH3:33])[CH:28]=[CH:27]3)[S:21]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:10])(=[O:34])=[O:35])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(C)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 11).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)=[O:39]>>[CH3:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][C:38]([C:40]1[CH:41]=[CH:42][C:43]([C:21]2[CH:20]=[CH:19][C:18]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:23][CH:22]=2)=[CH:44][CH:45]=1)=[O:39]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-4-phenyl-butan-1-ol and 4-(4-bromo-phenyl)-4-oxo-butyric acid methyl ester.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The compound was prepared as in Example 1 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (4.1 g) and 2-hydroxy-2-phenylethylamine (2.53 g). The compound was purified initially by column chromatography on silica gel and crystallised as the hydrobromide salt from methanol/diethyl ether m.p. 147°-160° as a 90:10 mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH:12][CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH3:11].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:12]([CH2:10][CH3:11])[CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNCCC(=O)NC
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CCC(=O)NC)c1nc(Cl)ncc1Br
Temperature: 100 °C
Yield: 66 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 1.14 g, 5.00 mmol), 3-ethylamino-N-methyl-propanamide (Intermediate 83; 0.642 g, 5.00 mmol) and triethylamine (0.71 mL, 5.10 mmol) were combined in acetonitrile (25 mL) and heated to 100° C. for 4 hrs. The solvent was removed under reduced pressure and the residue taken up in Ethyl Acetate, washed with water and purified by flash silica chromatography (companion, 40 g, 0-10% Methanol/DCM) to give the title compound as a white solid (1.06 g, 3.3 mmol, 66%).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH2:39])=[O:38].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:39][C:37]([C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[NH:34][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:38]
Reactant: O=C(O)c1csc(Br)n1
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.9 %

Procedure:
2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate VI.1 is obtained as a solid (1.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[C:5]#[N:6].O.[C:16](B(O)O)([CH3:18])=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[C:5]#[N:6])([CH3:18])=[CH2:17]
Reactant: COc1c(Br)cc(C#N)cc1[N+](=O)[O-]
Reactant: C=C(C)B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cc(C#N)cc([N+](=O)[O-])c1OC
Reaction time: 8 h

Procedure:
To a mixture of 3-bromo-4-methoxy-5-nitrobenzonitrile (6.26 g, 24.35 mmol) in dimethoxyethane (61 ml) was added water (16 ml), isopropenyl boronic acid (6.28 g, 73.1 mmol), potassium carbonate (10.10 g, 73.1 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.281 g, 0.244 mmol). The resulting mixture was heated to reflux and stirred at this temperature overnight under nitrogen. The reaction mixture was then concentrated, diluted with water, and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a Horizon Biotage, 65i Si column, eluting with 1 column volume of hexanes, followed by a linear gradient of ethyl acetate in hexanes from 0% to 100% over 10 column volumes to afford the title compound as a red oil.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10][NH2:11])=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:6]=1
Reactant: NCCC=Cc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccc(-c2ccccc2)cc1
Yield: 88.3 %

Procedure:
17 ml of methanol, 1.74 g of the product of Stage B and 0.17 g of 10% Pd on charcoal catalyst were placed in a hydrogenation apparatus and hydrogenation was maintained overnight. After filtering, washing and concentrating, the product was impasted in ethyl acetate, chilled, separated and dried under reduced pressure at 80° C. to obtain 1.55 g of the desired product melting at 260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10](O)=O>>[CH3:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=CO
Product: Cc1cccc2[nH]cnc12
Temperature: 70 °C
Yield: 90 %

Procedure:
A mixture of 3-methyl-1,2-benzenediamine (11.9 g) and formic acid (150 mL) was heated at 70° C. for 15 minutes. The solvent was removed under reduced pressure and the residual oil was stirred with water (100 mL) and sodium hydroxide solution (65 mL of 4.0 N) was added until the solution was just basic. The precipitate was filtered off, washed with water, and air dried to give 11.6 g (90%) of 4-methyl-1H-benzimidazole, mp 141°-145° C.
Reaction SMILES: [Cl-].[NH4+].C(O)(=O)C.[CH3:7][CH:8]([C:10]1[CH:17]=[C:16]2[N:12]([NH:13][C:14]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)=[N:15]2)[N:11]=1)[CH3:9].[OH-].[Na+]>O.CC(O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][C:14]2[NH:13][N:12]3[N:11]=[C:10]([CH:8]([CH3:9])[CH3:7])[CH:17]=[C:16]3[N:15]=2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2nc(CCCc3ccc([N+](=O)[O-])cc3)[nH]n2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)c1cc2nc(CCCc3ccc(N)cc3)[nH]n2n1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Reduced iron (6.7 g), ammonium chloride (0.53 g) and acetic acid (0.57 ml) were added to a mixed solvent of 2-propanol (40 ml) and water (8 ml), and the resulting mixture was heated over a steam bath and refluxed. To the mixture was further added the Nitro Compound (C) obtained in the step (3) above (6.27 g) and the reflux was further continued for 30 minutes. Sodium hydroxide (3.0 g) was dissolved in water (30 ml) and this solution was added to the above mixture. The resulting mixture was stirred and then filtered to remove insolubles. To the filtrate was added water (100 ml) and acetic acid (5 ml) and the resultant mixture was stirred. The resulting precipitated crystals were filtered and washed with water and dried to obtain 5.37 g (95%) of Amino Compound (D) as pale orange crystals (m.p.: 143.5°-144.5° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH:39]=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CO.ClCCl>[OH:40][CH2:39][CH2:38][CH2:37][CH:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([NH:23][S:20]([C:6]3[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH2:12][S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:21])=[O:22])=[O:41])=[CH:30][CH:29]=2)[CH2:36][CH2:35]1
Reactant: O=CCCC1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCC(CCCO)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 226 (15 mg, 0.025 mmol) in methanol (0.5 mL) and dichloromethane (2 drops) at 0° C. was treated with NaBH4 (24 mg, 0.6 mmol), stirred for 1 hour, warmed to room temperature, and stirred for 90 minutes. The mixture was treated with water and filtered. The filter cake was treated with dichloromethane (5 mL) and methanol (1 drop), stirred for 2 hours, and filtered. The filter cake was washed with diethyl ether, and dried under vacuum to provide the desired product. MS(ESI(−)) m/e 597 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.49 (d, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.71 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 6.95 (d, 1H), 6.90 (d, 2H), 4.34 (t, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3.39 (m, 2H), 3.25 (m, 2H), 2.65 (m, 2H), 1.71 (m, 2H), 1.45 (m, 2H), 1.25-1.11 (m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCO[CH2:16][CH2:15]1.Cl>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:15][CH3:16])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
4.9 g of quinoline-6-carboxylic acid was stirred in 80 ml of ethanol. 40 ml of dioxane containing 4 M of hydrogen chloride was added to the obtained mixture. After stirring at 70° C. overnight, the solvent was evaporated and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.[Pd].C(O)C>[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Product: c1ccc2c(c1)CCC1(CCNCC1)O2
Yield: 208.5 %

Procedure:
To a stirred solution of the spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (53 mg, 0.21 mmol) in methanol (5 mL) at 0° C., was added sodium borohydride (38 mg, 1 mmol) in several portions. After 30 minutes the mixture was evaporated and then treated with concentrated hydrochloric acid (2 mL) for 30 min. Evaporation gave a residue which was hydrogenated with palladium on carbon (10%, 10 mg), H2 (1 atm) in ethanol for two hours. Filtration to remove the catalyst gave the crude intermediate (89 mg) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28]>>[C:27]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and mono-methyl succinate to yield (3aR,4S,7aR)-1-(methoxycarbonyl)-4-(m-tolylethynyl)octahydro-1H-indol-4-yl methyl succinate. MS [M+H]=296 (ester elimination ion); RT=6.178 min; L-MS Method II