Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@H](C)[C@@H](C2C=CC=CC=2)O1)/[CH:2]=[CH:3]\[CH3:4].[CH:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:4][C@@H:3]([CH:2]=[CH2:1])[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C/C=C\C[Si]1(Cl)O[C@H](c2ccccc2)[C@@H](C)N1C
Reactant: O=CCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C[C@H](C)[C@@H](O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
Enantioselective crotylation of dihydrocinnamaldehyde to give (3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solution of (4R,5R)-2-((cis)-but-2-enyl)-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (0.431 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde (0.132 mL, 1.0 mmol). The reaction mixture was allowed to stir for 12 hours at −10° C. To this solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated. HPLC analysis of the residue at this stage revealed a syn:anti diastereoselectivity of 10:1, and an enantiomeric excess for the major syn product of 81%. The residue was purified by chromatography on silica gel to afford 0.116 g (61%) of (3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol (81% ee).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C=O)C>C(Cl)Cl>[C:5]1([CH:11]([CH2:15][CH3:16])[C:12]([Cl:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCC(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C(=O)Cl)c1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Thionyl chloride (0.12 mol) in 60 mL of CH2Cl2 was added to a stirred solution of 2-phenylbutyric acid (16.4 g, 0.10 mol). A catalytic amount of DMF was added and the reaction was allowed to continue overnight at room temperature. The volatiles were removed under vacuum and the residual liquid was vacuum distilled to yield 12.4 g (68%) of 2-phenylbutyryl chloride. IR (neat) 1798 cm-1 (C=O).
Reaction SMILES: CC[C@@H]([C@H](NC([C@@H](NC(CN)=O)CC1C=CC(O)=CC=1)=O)C(NCC(N[C@H](C(N[C@H](C(O)=O)CCCN=C(N)N)=O)CO)=O)=[O:7])C.[CH2:47]([CH2:76][N:77]=[C:78]([NH2:80])[NH2:79])[CH2:48][C@H:49]([NH:71][C:72]([CH2:74][NH2:75])=[O:73])[C:50]([NH:52][CH2:53][C:54]([NH:56][C@H:57]([C:62](N[C@H](C(O)=O)CO)=[O:63])[CH2:58][C:59]([OH:61])=[O:60])=[O:55])=[O:51]>>[CH2:47]([CH2:76][N:77]=[C:78]([NH2:80])[NH2:79])[CH2:48][CH:49]([NH:71][C:72]([CH2:74][NH2:75])=[O:73])[C:50]([NH:52][CH2:53][C:54]([NH:56][CH:57]([C:62]([OH:63])=[O:7])[CH2:58][C:59]([OH:61])=[O:60])=[O:55])=[O:51]
Reactant: NCC(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Product: NCC(=O)NC(CCCN=C(N)N)C(=O)NCC(=O)NC(CC(=O)O)C(=O)O

Procedure:
GYIGSRY; GRGDF, GRGDY; GREDV; GYIGSR; GREDVY; and GRGDS;
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][C:32]1[CH2:33][NH:34][CH2:35][CH2:36][CH:37]=1>C(OCC)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][C:32]1[CH2:33][N:34]([CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:35][CH2:36][CH:37]=1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2[nH]cc(CC3=CCCN(CCC(=O)c4ccc(F)cc4)C3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.9 ml; 0.0063 mol) was added to a solution of 3-chloro-4'-fluoropropiophenone (1.2 g; 0.0063 mol) in diethyl ether (10 ml). The resulting mixture was stirred for 3 hours at room temperature. Then the mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up with a mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (0.79 g; 0.0028 mol), triethylamine (0.8 ml; 0.0057 mol) in methylene chloride (20 ml). The reaction mixture was refluxed for 4 hours. Then the reaction was concentrated under vacuum and the residue was triturated with 1N hydrochloric acid. The aqueous phase was decanted, and the guming solid was twice washed with water and triturated with diethyl ether. The title compound hydrochloride was collected by filtration, washed with diethyl ether and recrystallized with a mixture (1/2) of ethyl acetate/acetone. 0.86 g of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5](OC1C=C(NS(N2CCCC2)(=O)=O)N=C(S[CH2:24][C:25]2[CH:30]=C[CH:28]=[C:27](F)[C:26]=2F)N=1)C)[CH3:2].[BH4-].[Li+]>C1COCC1>[CH3:2][CH2:1][O:3][CH2:4][CH3:5].[CH3:28][CH2:27][CH2:26][CH:25]([CH3:30])[CH3:24]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: CCOCC

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1-pyrrolidinylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of step i) (0.38 g), THF (8 mL) and 2 M lithium borohydride in THF (1.3 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase). The resulting oil was titurated with methanol, toluene, DCM, then ether/iso-hexane to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 120 %

Procedure:
To a −78° C. solution of 2.8 mL (20.0 mmol) of diisopropylamine in 40 mL of dry tetrahydrofuran was added 13.75 mL (22 mmol) of 1.6 M n-butyllithium in hexanes. The reaction was let warm to 0° C. and then cooled to −78° C. A solution of 2.7 mL (20 mmol) of ethyl cyclobutanecarboxylate in 10 mL of tetrahydrofuran was added dropwise and the reaction let warm to 0° C. The reaction was stirred for 15 min before being cooled to −78° C. To the solution was added 3.1 mL (26 mmol) of benzyl bromide dropwise and the reaction stirred for 15 min before being let warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 5.24 g of crude ethyl 1-benzylcyclobutanecarboxylate. The crude product was dissolved in 100 mL of tetrahydrofuran and cooled to 0° C. To this solution was added dropwise 14.1 mL (14.1 mmol) of 1M lithium aluminum hydride in tetrahydrofuran. The reaction was stirred for 1 h before being carefully quenched with brine. The mixture was filtered through a celite plug and the filter cake washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 1.6 g (45%) of ethyl (1-benzylcyclobutyl)methanol. 1H NMR (300 MHz, DMSO-d6) δ 7.18-7.34 (m, 5H), 4.63 (t, J=5 Hz, 1H), 3.24-3.25 (d, J=5H, 2H), 2.71 (s, 2H), 1.66-1.79 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:25](=[O:29])[C:26]([NH2:28])=[O:27])=[C:9]([CH3:24])[N:10]2[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[OH-].[Na+].CO.C(OCC)(=O)C>O>[NH2:28][C:26](=[O:27])[C:25]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:10]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:9]=1[CH3:24])=[O:29]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A mixture of 420 mg (0.94 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 5 mL of 1N NaOH and 15 mL of MeOH was heated to maintain reflux for 0.17 hours, cooled to room temperature and stirred 0.5 hours. Ethyl acetate and water was added, the aqueous layer separated, made acidic to pH 2-3 with 1N HCl, and the mixture extracted with ethyl acetate two times. The part that was not soluble was filtered. The filtrate was dried (MgSO4) and concentrated. The remaining solid was washed with a small volume of ether/methylene chloride and the insoluble material filtered and combined with the filtered material above to give 351 mg (86% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid, mp, 236°-239° C.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][SH:25].[OH-:26].[K+]>C(O)C>[NH:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:18])[CH2:16][CH2:17][S:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][S:25][CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=CC(=O)Nc1ccc(Nc2ccccc2)cc1
Reactant: SCCOCCS
Agent: [K+]
Solvent: CCO
Product: O=C(CCSCCOCCSCCC(=O)Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 100 grams of N-(4-anilinophenyl) acrylamide in 1200 milliliters of ethanol was added 29 grams of 2-mercaptoethyl ether. A solution of 5 grams of potassium hydroxide in 50 milliliters of ethanol was added at 20°C. Within 5 minutes the temperature began to rise, reaching a maximum of 29°C. after about 15 minutes. As the temperature began to rise, product began to precipitate. The reaction mixture was stirred for 1 hour and the solid product was then filtered off and allowed to dry. There was obtained 123 grams (95 percent of theory) of product which melted at 154°-156° C.
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C(OCC)C>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25.8 mg of the isomer having a high Rf value of L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucine tert-butyl ester was dissolved in 0.2 ml of dichloromethane. Then, 0.1 ml of TFA was added thereto, and the mixture was stirred at room temperature for 4 hours. Then, the reaction solution was concentrated under reduced pressure. The residue thereby obtained was diluted with diethyl ether and concentrated under reduced pressure. This operation was repeated to obtain 22.9 mg of L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucine.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21].N1CCCCC1>C(O)C>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1C
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (398 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed tube at 60° C. for 10 hours. The reaction was concentrated, the residue was dissolved in a mixture of water and methanol and then acidified with 1N HCl. The resulted precipitate was collected by vacuum filtration, washed with methanol and dried to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]([NH2:24])=[CH:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[CH:11][CH:10]=1.O.C(OCC)(=O)C>OS([O-])=O.[Na+].C(O)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:17]2[N:24]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[N:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[C:16]=2[CH:21]=1
Reactant: COc1ccc(N)c(Nc2ccc(F)cc2)c1
Reactant: O=Cc1ccsc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccsc3)n(-c3ccc(F)cc3)c2c1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
7.48 g of thiophene-3-aldehyde was stirred in 65 ml of 40% NaHSO3 solution for two hours. After 15 g of N2-(4-fluorophenyl)-4-methoxybenzene-1,2-diamine in 50 ml of ethanol was added, it was boiled for 4 hours, and stirring was continued overnight. The batch was dispersed between water and ethyl acetate, and the organic phase was washed with water. After drying on sodium sulfate and concentration by evaporation of the filtrate, 18.1 g of crude 6-methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole is obtained.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=[O:37])[CH3:36].[Na+].NC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C.O=CCNC(=O)OC(C)(C)C>C(Cl)Cl>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:11]([N:10]1[C:35](=[O:37])[CH2:36][CH2:6][NH:7][CH2:8][CH2:9]1)[CH:12]([CH3:14])[CH3:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NCC=O
Agent: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation of {2-[1-(3-Benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester: Sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added to a solution containing 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (185 mg, 0.54 mmol) (prepared using the general procedure described in WO 0130768) and tert-butyl N-(2-oxoethyl)carbamate (103 mg, 0.65 mmol) in CH2Cl2 (5.4 mL). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 (10 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (5–10% EtOAc in hexane) gave the title compound (105 mg) as a white solid: MS (ES) m/e 485 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:36]=[CH:35][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=2[CH2:51][Cl:52])[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46]>>[ClH:52].[ClH:52].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:51][C:50]2[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=2[C:41]2[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=2)=[CH:35][CH:36]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Product: CCCCc1ccc(N(Cc2ccccc2-c2cc(OC)c(OC)c(OC)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.[CH3:42][C:43]1[NH:52][C:51]2[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[NH:48][CH2:47][CH2:46][C:45]=2[N:44]=1>ClCCl.CN(C=O)C>[CH3:7][C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:48]3[CH2:47][CH2:46][C:45]4[N:44]=[C:43]([CH3:42])[NH:52][C:51]=4[C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]3=4)=[O:26])=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1
Reactant: Cc1nc2c([nH]1)-c1ccccc1NCC2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(CCC(=O)N3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Oxalyl chloride (0.049 ml, 0.55 mmol) was added slowly to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (100 mg, 0.28 mmol) in dichloromethane (10 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was redissolved in dichloro-methane (10 ml) and DIEA (0.144 ml, 0.84 mmol) then 2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5 (55 mg, 0.28 mmol) was added. The mixture was stirred for 20 h at room temperature then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white fluffy solid identified as the title compound (42 mg, 28%).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: c1cn(C2CCNCC2)nn1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COc2c(N3CCC(n4ccnn4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (100 mg) and DBU (80 mg) were added to a suspension of (-)-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs followed by stirring at room temperature for an additional 48 hrs. The reaction mixture was concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and dried to yield 30 mg of desired product. m.p. 254°-255° C. (dec). 1H NMR (TFA) δ: 9.4 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (d, 11.43Hz, 1H), 5.6-5.1 (m, 2H), 5.0-4.7 (m, 2H), 4.45-4.05 (m, 4H), 3.1-2.6 (m, 4H), 1.86 (d, 6.3Hz, 3H). Anal. calcd. for C 20 H20FN5O4 . H2O; C, 55.68; H, 5.14; N, 16.23.Found C, 55.88; H, 4.762; N, 15.92.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH2:26]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:54])C(=O)C1>C(Cl)Cl>[Br:54][CH2:26][C:8]1[N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[C:10]2[C:15]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)c(-c3ccccc3)c3ccccc32)cc1
Reaction time: 2 h
Yield: 28.8 %

Procedure:
To a solution of [3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]methanol (1.31 g, 3.47 mmol) and triphenylphosphine (1.09 g, 4.16 mmol) in DCM (30 mL) at RT under a nitrogen atmosphere was added NBS (240 mg, 4.16 mmol) and stirring was continued for 2 h. Volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a gum (440 mg, 29%). 1H NMR (CDCl3, 400 MHz): δ 8.16 (1H, dt, J=8.48, 0.84 Hz), 7.92-7.88 (2H, m), 7.60-7.49 (4H, m), 7.48-7.37 (3H, m), 7.28-7.22 (3H, m), 5.05 (2H, s), 2.38 (3H, s)
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Li+].[CH2:8]1[O:18][C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9]1.C[OH:20]>O>[O:10]1[C:11]2([CH2:16][CH2:15][C:14](=[CH:2][C:3]([O:4][CH2:5][CH3:1])=[O:20])[CH2:13][CH2:12]2)[O:18][CH2:8][CH2:9]1
Reactant: C1CCOC1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CO
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of THF (18 mL) under argon was added 0.38 g (47.8 mmol, 5 equiv) of LiH, followed by slow addition of 8.78 g (47.8 mmol, 5 equiv) of triethyl phosphonoacetate. The solution was stirred at rt for 1 h and 1.49 g (9.6 mmol, 1 equiv) of 1,4-cyclohexanedione mono-ethylene ketal was added and the solution was heated at 65° C. for 16 h. Upon cooling the solution was treated with MeOH (10 mL) and water (5 mL) and concentrated in vacuo. The resulting yellow oil was purified by silica gel chromatography eluting with 4:1 Hex/EtOAc to yield 1.89 g (93%) of a clear oil. 1H-NMR (CDCl3-d) δ 5.67 (s, 1H), 4.16 (t, 2H), 3.99 (m, 4H), 3.02 (m, 2H), 2.39 (m, 2H), 1.78 (m, 4H), 1.29 (t, 3H); LCMS RT=2.56 min; [M+H]+=226.9.