Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][O:5]1.[CH3:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:11][O:12][CH2:13][N:8]1[CH2:9][C@@H:4]([CH3:3])[O:5][CH2:6][C:7]1=[O:10]
Reactant: COCCl
Reactant: C[C@@H]1CNC(=O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1C[C@@H](C)OCC1=O
Reaction time: 0.5 h

Procedure:
To sodium hydride (63%, 4.4 g, 116 mmol) suspended in tetrahydrofuran (100 mL), a solution of (6R)-6-methylmorpholin-3-one (EP350002) (12.1 g) in tetrahydrofuran (50 mL) was added dropwise over 30 minutes under ice cooling. The mixture was stirred at the same temperature for 30 minutes and then further stirred at room temperature for 30 minutes. A solution of chloromethyl methyl ether (10 mL) in tetrahydrofuran (50 mL) was added dropwise thereto over 30 minutes under ice cooling. The mixture was stirred for 30 minutes under ice cooling and then stirred overnight at room temperature. An appropriate amount of water for partition was added thereto, followed by several extractions with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate=40/60) to obtain the title compound (7.86 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran and under an atmosphere of nitrogen was cooled to -30° C. in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.30 mole) was added over 1 hr and the mixture was stirred for an additional 30 min at -30° C. The reaction mixture was allowed to warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of 4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid was collected. The aqueous mixture was extracted with several portions of methylene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (67.9% yield) of title compound as a white, crystalline solid: mp 158°-159.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:17]2[C:13]([S:14][C:15]([C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[CH:16]2)=[CH:12][N:11]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([C:15]3[S:14][C:13]4=[CH:12][N:11]=[C:10]([CH2:9][OH:8])[N:17]4[CH:16]=3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(CO[Si](C)(C)C(C)(C)C)ncc4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(CO)ncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 799 mg of 4-nitrobenzyl (1S,5R,6S)-2-(5-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 20 ml of THF were added 1.1 ml of acetic acid and 6.5 ml of 1 M solution of tetra-n-butylammonium fluoride in THF under the atmosphere of argon, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and diluted with 100 ml of ethyl acetate, 100 ml of aqueous saline and a saturated aqueous sodium hydrogen carbonate solution to adjust pH to 7.8. The organic layer was separated, washed with aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 619 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9](O)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([SH:44])[N:37]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[O:1]([C:8]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH:9]([S:44][C:38]1[N:37]=[C:36]([O:35][CH3:34])[CH:41]=[C:40]([O:42][CH3:43])[N:39]=1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
7.2 g (25 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (comp. 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in 100 ml of DMF and added dropwise to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 nm mmol) of sodium bicarbonate in 100 ml of DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for a further 2 hours, the mixture is poured into 1 1 of ice-water, and the precipitate is filtered off with suction. Drying results in 4.2 g of a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C([N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH3:20])(C)C>C(Cl)Cl>[CH3:22][CH:21]([N:18]([CH2:19][CH2:20][CH2:20][CH2:19][NH:18][CH:21]([CH3:22])[CH3:23])[S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:23]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCCCCN(C(C)C)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Trifluoromethyl benzene sulfonyl chloride (0.104 m, 25.35 g) in methylene chloride (100 ml) was added dropwise to a solution of N,N'-diisopropylbutane,1,4-diamine (0.104 m, 17.86 gm) and diisopropyl ethyl amine (0.104 m, 13.40 g) in methylene chloride (500 ml). The reaction was stirred overnight. The reaction was washed with water, aqueous sodium bicarbonate and then brine and then stripped. The residue was dissolved in diethyl ether, filtered through Supercel to yield the title compound. Treatment with isopropanol/HCl provided the hydrochloric acid salt of the title compound, 14.64 gms, m.p. 175°-176.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]([CH3:24])[CH3:23])[S:14]1(=[O:26])=[O:25])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[CH3:27][NH2:28]>>[Cl:12][C:7]1[CH:6]=[C:5]([C@H:4]([N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH3:23])[CH3:24])[S:14]2(=[O:25])=[O:26])[CH2:3][CH2:2][NH:28][CH3:27])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: CC(C)N1c2ccccc2N([C@H](CCCl)c2cc(F)cc(Cl)c2)S1(=O)=O
Reactant: CN
Product: CNCC[C@H](c1cc(F)cc(Cl)c1)N1c2ccccc2N(C(C)C)S1(=O)=O
Yield: 70 %

Procedure:
1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1.75 g, 4.19 mmol) and ethanolic solution of methylamine (33% in ethanol, 30 mL) was heated at 85° C for 4 hours with stirring in a sealed reaction vessel. Upon cooling, all volatiles were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (50 mL), washed with aqueous potassium carbonate (20 mL), dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion column chromatography (silica gel, 0-15% methanol/dichloromethane, with 0.5% triethylamine additive) gave 1.22 g (70%) of (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothia diazol-1(3H)-yl)-N-methylpropan-1-amine as a white foam, which was dissolved in dichloromethane (20 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 3.3 mL, 3.3 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl)-N-methylpropan-1-amine hydrochloride as a white powder. MS (ES) m/z 411.9 ([M+H]30 ); HRMS: calculated for C19H23CIFN3O2S+H+, 412.1256; found (ESI, [M+H]30), 412.1266.
Reaction SMILES: C1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[NH2:8])CCCCC1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:9]1([N:8]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C(N)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of (+/−)-cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (80.0 mg, 0.237 mmol) in N,N-dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110° C. and stirred overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate (20 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.06 (s, 1H), 7.79-7.82 (m, 2H), 7.43 (s, 1H), 7.33-7.36 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.8 Hz, 1H), 5.39 (d, J=6.8 Hz, 1H), 4.74 (m, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 1.85-1.88 (m, 1H), 1.58-1.72 (m, 5H), 1.05-1.19 (m, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:2]=1.C(=O)([O-])O.[Na+].[CH2:28](Br)[CH3:29].O>CN(C)C=O>[CH2:28]([O:12][C:11](=[O:13])[CH2:10][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:22])[CH3:29]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)Nc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.8 %

Procedure:
To a suspension of N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid (1 g) and sodium hydrogen carbonate (0.54 g) in N,N-dimethylformamide (5 ml) was added to a solution of ethyl bromide (1.76 g) in N,N-dimethylformamide (5 ml). After stirring at room temperature for 4 days, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid ethyl ester (0.63 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C=NC=C(C(F)(F)F)C=3)[CH2:13][CH2:12]2)N=1.Br[C:28]1C=NC=C(C(F)(F)F)C=1.Cl[C:39]1[N:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:40]=1[C:41]#[N:42].CC1C=CC=C(C#CC=C2CCNCC2)N=1>>[CH3:47][C:45]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([N:14]2[CH2:13][CH2:12][C:11](=[C:10]([CH3:28])[C:9]#[C:8][C:4]3[CH:1]=[CH:2][CH:7]=[CH:6][CH:5]=3)[CH2:16][CH2:15]2)[N:46]=1
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc(C(F)(F)F)c3)CC2)n1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: CC(C#Cc1ccccc1)=C1CCN(c2nc(C)ccc2C#N)CC1
Yield: 35 %

Procedure:
The title compound was synthesized following the procedure described for the Compound of Example 262 replacing 3-bromo-5-(trifluoromethyl)pyridine with 2-chloro-6-methylnicotinonitrile and the compound of Example 3 with Compound 253d. Purification by automated flash chromatography (Horizon™-Biotage) PE-EtOAc 9:1 afforded a colorless oil. Yield: 35%.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11]1.[CH:18]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:29]1[C:25]2[CH:26]=[CH:27][C:28]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH:33]3[CH2:34][CH2:35][N:36]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]([OH:16])=[O:17])[CH2:37][CH2:38]3)[C:24]=2[CH:32]=[CH:31][CH:30]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCC(=O)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.04 gram (0.36 millimole) of 4-dimethylaminopyridine, 0.94 gram (7.26 millimoles) of ethyl diisopropylamine, and 0.41 gram (3.63 millimoles) of glutaric anhydride were added successively to a solution of 1.00 gram (3.63 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine and the resulting mixture stirred at ambient temperature for two hours. The reaction mixture was diluted with 100 milliliters of methylene chloride and washed with aqueous hydrochloric acid and then with brine. The washed solution was dried over magnesium sulfate, the drying agent filtered and the solution evaporated in vacuo whereupon a foam was produced which when triturated with hot acetonitrile produced white crystals. The crystals were recrystallized from hot acetic acid/acetonitrile to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-δ-oxo-1-piperidinepentanoic acid product, m.p. 180°-186° C. The product had elemental analyses as follows:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br-:16].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCCCBr)ccc(C(C)=O)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(SCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C(C)=O)c1O
Product: [Br-]

Procedure:
The title compound is prepared analogously to Example 1 from 5-(4-acetyl-3-hydroxy-2-propylphenylthio)-pentyl bromide and triphenylphosphine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]6[S:37][CH:41]=[CH:40][CH:39]=6)[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1

Procedure:
The title compound was prepared from {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine and 2-thiopheneacetyl chloride using acylation conditions described in Example 36, Step H to generate the desired product in 76% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.42 (s, 1H), 8.83 (d, J=6.9 Hz, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.29 (d, J=6.6 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.35-7.47 (m, 5H), 7.03-7.13 (m, 4H), 6.52 (d, J=5.4 Hz, 1H), 3.99 (s, 2H), 2.87-2.99 (m, 3H), 2.66-2.72 (m, 2H), 2.21 (s, 6H). ES-LC/MS m/z=604 [M+H]+.
Reaction SMILES: [C:1]1([C:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.O1CCOCC1.Cl>[Zn].C1(C)C=CC=CC=1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 60 g of desoxyanisoin, 120 g of amalgamated zinc, 200 ml of dioxane, 100 ml of toluene and 200 ml of concentrated hydrochloric acid was refluxed for 24 hours. Another 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The reaction mixture was cooled to room temperature and the organic layer was separated and mixed with 300 ml of ethyl acetate. It was washed with water, dried over anhydrous magensium sulfate and concentrated to give 26 g of white waxy solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([CH:18]=O)=[C:10]3[CH:4]2[CH2:3]1.B#B.CO.C(O)(=O)C>O1CCCC1>[CH3:1][N:2]1[CH2:25][CH2:24][N:5]2[C:6]3[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]([CH3:18])=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccccc3Cn3c(c(C=O)c4ccccc43)C2C1
Agent: B#B
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)Cc1ccccc1N1CCN(C)CC21
Reaction time: 1 h

Procedure:
To a solution of 1.4 g of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxaldehyde in 35 ml tetrahydrofuran is added 17 ml of 1M diborane in tetrahydrofuran. The reaction mixture is heated at reflux temperature for 5 hours. The reaction is then treated with 10 ml methanol and 3.5 ml acetic acid and heating is continued for an additional 1 hour. The solvent is evaporated under reduced pressure and the residue is dissolved in methylene chloride and washed with 5% sodium hydroxide solution. The methylene chloride layer is separated and the solvent evaporated under reduced pressure to yield 1,3,4,16b-tetrahydro-2,16-dimethyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine which is converted to the hydrochloride salt, mp 293°-298° dec.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH2:25][CH2:24][OH:23])[CH:28]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1ccc(C(=O)O)cc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OC)c(OCCO)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brown solid. MS 498 (MH+).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH3:8][CH:9]([S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([C:40]([NH2:42])=[O:41])[CH:25]=[C:26]([C:29]4[CH:33]=[C:32]([CH2:34][N:35]([CH3:39])[CH2:36][CH2:37]C)[S:31][CH:30]=4)[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:10].CNCCC>>[CH3:10][CH:9]([S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([C:40]([NH2:42])=[O:41])[CH:25]=[C:26]([C:29]4[CH:33]=[C:32]([CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][O:4][CH3:3])[S:31][CH:30]=4)[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)C(C)C)CC4)c3c2)cs1
Agent: CCCNC
Product: COCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)C(C)C)CC4)c3c2)cs1
Yield: 69.4 %

Procedure:
The title compound was prepared according to the general procedure of 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate, substituting methyl[2-(methyloxy)ethyl]amine (89 mg, 1.0 mmol) for methyl(propyl)amine to afford 37.0 mg of the title compound (69.4%).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([OH:14])[CH:6]=1.C(=O)=O.[ClH:18].[H][H]>C(O)C.O1CCCC1.[Pd]>[ClH:18].[ClH:18].[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:3])=[CH:6][C:7]=1[OH:14]
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccc(N)c(O)c1
Yield: 97 %

Procedure:
A solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.9 g, 30 mmol) in ethanol (100 mL) and tetrahydrofuran (100 mL) is degassed with solid carbon dioxide, then charged with 10% palladium on carbon (500 mg) and concentrated hydrochloric acid (5.5 mL). The mixture is shaken under 50 psi hydrogen gas until consumption of hydrogen had ceased. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 2-amino-5-(aminomethyl)phenol dihydrochloride (6.1 g, 97%).