Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH:24]=[N:23][C:22]2[CH:29]=[CH:30][CH:31]([CH3:34])[C:32](=[O:33])[C:21]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[CH2:26][C:25]([CH3:27])([CH3:28])[CH:24]=[N:23][C:22]3[CH:29]=[CH:30][CH:31]([CH3:34])[C:32](=[O:33])[C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1C=CC2=C(C1=O)C(N)CC(C)(C)C=N2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1C=CC2=C(C1=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)CC(C)(C)C=N2

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3) and crystallization from acetonitrile.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][O-:25].[Na+]>>[CH3:24][O:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)nnc2c(=O)[nH]1

Procedure:
In a similar manner to Example 78, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4] triazine (0.5 g) was treated for 3 hours with sodium methoxide (prepared from sodium, 0.17 g, and methanol) to afford the title compound, 0.34 g, m.p. 234-235° C. (recrystallized from methanol).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=3)[C:24]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(NS(C)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A solution of 4-Methanesulfonylaminophenylboronic acid (24 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA40 (0.9 mg, 3% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.6 g of 4-chloro-1-naphthol, 27.62 g of 4-fluoroacetophenone, and 55.2 g of potassium carbonate in 250 ml of N,N-dimethylacetamide are heated under Argon with vigorous stirring at 150°-155° C. overnight. After cooling to room temperature, 500 ml of water is added and the mixture is extracted with three 150 ml portions of benzene. The combined extracts are washed with two 150 ml portions of 5% NaOH, three 150 ml portions of 10% HCl, two 150 ml portions of water, 150 ml of saturated NaHCO3, 150 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a light brown solid, which is extracted with 800 ml of hot hexane to give the product as a tan solid, mp 98°-105° C. Recrystallization from 15:1 hexane-chloroform gives cream colored plates, mp 100°-104.5° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@@H](C1C=CC=CC=1)CN>CC(CC(C)=O)C>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
That is, (±)-2-(3-benzoylphenyl)propionic acid (12.7 g, 50 mmol) was dissolved in MIBK (76 ml) and (S)-(+)-3-methyl-2-phenylbutylamine (4.9 g, 30 mmol) was added dropwise at 40° C. This reaction solution was stirred at 35° C. to 40° C. for one hour, followed by at room temperature for 5 hours and then at 10° C. to 15° C. for one hour. Then, the crystal precipitated was filtered, and the filter cake was washed with cold MIBK (30 ml) and dried to give a diastereomer salt (8.34 g) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 80%. Melting point: 129°-131° C. Optical purity: 94.3% e.e.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].[H][H]>C1COCC1.O>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][OH:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCC(CO)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-6-tert-butoxycarbonylamino-hexanoic acid (Cbz-Lys(Boc)-OH) (Chem-Impex International, 3.8 g, 10 mmol) in THF (25 mL) in a 100 mL round flask was added 1,1′-carbonyldiimidazole (CDI) (1.7 g, 10.5 mmol) at room temperature. After 20 minutes, the THF solution was transferred via a Teflon cannula (+=2 mm) to a stirred solution of sodium borohydride (0.75 g, 20 mmol) in water (10 mL) in a 1 L round flask immersed in a water bath at 5-10° C. The addition caused a strong evolution of hydrogen gas and the mixture was stirred for a couple of hours. The volatiles were then removed on a rotovap, and the residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted successively with cold 1 N HCl (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL), and was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was then pass through a one inch flash pad of silica gel, and concentrated to provide a colorless solid (3.3 g, 91%), TLC Rf=0.24 (95:5:2 EtOAc:MeOH:H2O).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3]1
Reactant: OC1CCC(O)CC1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)OC1CCC(O)CC1
Yield: 25 %

Procedure:
1,4-cyclohexanediol (20.0 g, 172.4 mmol) was dissolved in dichloromethane (200 mL). Cinnamoyl chloride (7.2 g, 43.1 mmol) dissolved in 50 ml dichloromethane was then slowly added. After 2 h of mixing, triethyl amine (5.3 g, 52 mmol) was added slowly. After 48 h of mixing, the solution was washed three times with dilute HCl (1 M) and two more times with H2O before it was dried over MgSO4 and filtered. The product was then dissolved in methanol which resulted in precipitation of the byproduct. After filteration and evaporating the solvents from the filtrate, the product was a obtained as yellow-orange viscous liquid, which was used without further purification. Yield: 25-40%.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.Cl.Cl.[CH3:25][NH:26][CH:27]1[CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1[C:20]([N:29]2[CH2:30][CH:27]([NH:26][CH3:25])[CH2:28]2)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CNC1CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Agent: Cl
Product: CNC1CN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)C1
Yield: 84.5 %

Procedure:
7,9-Difluoro-1-methyl-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 30, but starting with 1.5 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.2 g of 3-(methylamino)azetidine dihydrochloride. 1.54 g of 7,9-difluoro-1-methyl-8-(3-methylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 302° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.ClCCl.[OH-].[Na+]>CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCCCCCOCCCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-quinolinebutanol (2.56 g), 1,6-dibromohexane (5 ml), dichloromethane (2 ml), TAB (150 mg) and 50% aqueous sodium hydroxide (5 ml) was stirred at room temperature for 18 h. Ether (40 ml) was added and the organic phase separated, washed with water (20 ml), brine (20 ml), dried and evaporated in vacuo to an oil. The oil was purified by chromatography over a column of silica (Merck 60, Art. 7734). Elution with hexane and hexane-ether (9:1) followed by hexane-ether (1:1) afforded the title compound (2.12 g) as a colourless oil, t.l.c. (diethyl ether), Rf 0.50.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][NH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][N:21]([CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH2:22]2.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](O)=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH:23]3[CH:18]([N:17]([CH3:16])[C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)=[CH:37][CH:36]=1)#[N:35]
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Reactant: CC(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1,3-Dicyclohexylcarbodiimide on N-methylpolystyrene (0.67 g of 2.39 mmol/g, 1.74 mmol) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Peparation G; 74.6 mg, 0.25 mmol) in DMF (3.0 mL). A solution of 3-methylbutyric acid (105.0 mg, 1.02 mmol) in DCM (1.0 mL) was added, and the mixture was stirred overnight at rt, followed by a further 72 h at 50° C. Polystyrene isocyanate (150 mg) and DCM (1.5 mL) were added, and this mixture was stirred for 1.5 h. K2CO3 (75 mg) was added and the mixture stirred for an additional 5 h. The solvents were evaporated and DCM (3 mL) was added to the resulting residue. This mixture was added to an ion-exchange solid-phase extraction plug (CBA). The plug was washed with DCM:MeCN (4:1; 10 mL). The product was then eluted with DCM:MeOH:TEA (90:5:5; 7.5 mL) to give 75 mg (70.9%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:10][Si:11]([Cl:18])([Cl:17])[CH2:12][CH2:13][SiH:14]([Cl:16])[Cl:15]>>[Cl:10][Si:11]([Cl:18])([Cl:17])[CH2:12][CH2:13][Si:14]([Cl:16])([Cl:15])[CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Reactant: C=CCc1ccccc1
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CCCc1ccccc1
Temperature: 80 °C

Procedure:
18.77 g (0.159 mol) allylbenzene and 50 μl H2PtCl6/IPA solution were added to a 100 ml vessel. Solution was heated up to 80° C. and 41.85 g (0.159 mol) 1,1,1,4,4-pentachloro-1,4-disilabutane was added slowly during 30 min. Heat was switched off when exothermic reaction was observed. Temperature during the addition was kept below 130° C. After addition heat was again switched on and solution was stirred for an hour at 110° C. After that product was purified by distillation. B.p. 137° C./0.8 mbar. Yield 35.10 g (58%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.C(OP([CH2:21][C:22](=[O:27])[NH:23][CH:24]1[CH2:26][CH2:25]1)(=O)OCC)C>>[CH:24]1([NH:23][C:22](=[O:27])/[CH:21]=[C:9]2\[CH2:8][CH2:7][CH2:6][C:5]3[C:10]\2=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]1
Reactant: CCOP(=O)(CC(=O)NC1CC1)OCC
Reactant: O=C1CCCc2ccc(F)cc21
Product: O=C(/C=C1\CCCc2ccc(F)cc21)NC1CC1

Procedure:
This compound was prepared in an analogous manner to Example 12f with the replacement of 5-fluoro 1-tetralone and diethyl (cyclopropylcarbamoyl)methyl phosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silca gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide. m.p., 122.8-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd J=11.0 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m, 2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[CH2:24]([O:26][C:27](=[O:36])[CH:28](Br)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25]
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Reactant: CCOC(=O)C(Br)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Yield: 75.9 %

Procedure:
To the solution of 75 g (0.28 mol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole in 750 ml N,N-dimethylformamide 116 g (0.33 mol) cesium carbonate and 88 g (0.35 mol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added. The mixture was heated to 100° C. and after stirring for 90 min. another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 6 h another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 22 h (total reaction time) the reaction mixture was cooled to 30° C. and was poured on 1 L ice water and 2 L ethyl acetate. The phases were separated and the aqueous phase extracted with 500 mL ethyl acetate. The combined organic phases were washed three times with 500 ml ice water and once with brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using n-heptane:ethyl acetate (9:1 v/v) as eluant. The product-containing fractions were pooled and the solvent evaporated until a suspension had formed. The suspension was cooled in an ice bath and filtered to give 92 g (75%) of the desired product as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH2:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([CH3:16])[C:14]=1[F:15].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH:6][C:11]1[CH:12]=[C:13]([CH3:16])[C:14]([F:15])=[C:9]([CH3:8])[CH:10]=1)[CH3:5]
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1cc(B(O)O)cc(C)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 39 h
Yield: 37.5 %

Procedure:
To a suspension of (R)-2-amino-propionic acid methyl ester (0.200 g, 1.940 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.652 g, 3.880 mmol), Cu(OAc)2 (0.388 g, 2.134 mmol), and molecular sieves 4 Å (1.456 g) in 15 mL of dichloromethane, was added triethylamine (0.54 mL, 3.880 mmol). After stirring at room temperature under O2 for 39 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as brown oil (0.164 g, 38% yield). LC-MS: tR=8.1 min; m/z 226 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Cl:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(OCCCl)cc1

Procedure:
4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo. After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro-(2-chloroethoxy)benzene (909 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15].CCN(CC)CC>C1COCC1>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: CC(C(=O)O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNC(=O)C(C)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
N,N′-Carbonyldiimidazole (22.65 g, 140 mmol) was added to commercially available 2-(4-hydroxyphenyl)propionic acid (21 g, 127 mmol) in THF (100 mL). Gentle warming and gas evolution was observed. The resulting mixture was stirred for 3 h. Allylamine (10.9 g, 190.5 mmol) and Et3N (19.2 mL, 190.5 mmol) were added dropwise, and the mixture was stirred overnight. The reaction was quenched with water (200 mL) and the organic phase was extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (elution with ethyl acetate). Phenol 49.1 was obtained as a white solid. MS ESI m/e: 206 (M−H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C(Cl)(Cl)Cl.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([S:9][C:10]([F:11])([F:13])[F:12])[CH:7]=1
Reactant: CNc1ccc(SC(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNc1ncc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a mixture of methyl-(5-trifluoromethylsulfanylpyridine-2-yl)-amine (1.52 g) and chloroform (24 mL), N-bromosuccinimide (1.43 g) was added, and stirred at room temperature for 1 hour. Into the reaction mixture, water was poured, and extracted with chloroform. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.96 g of (3-bromo-5-trifluoromethylsulfanylpyridine-2-yl)-methylamine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[N:11]2)=[CH:6][CH:5]=1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1>C1COCC1>[CH3:28][O:27][C:25]([C:22]1[CH:21]=[N:20][C:19]([O:16][CH2:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[N:11]=[N:12][C:13]=2[CH3:17])=[CH:24][N:23]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2c(C)nnn2-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a suspension of NaH (55% in oil, 116 mg, 2.7 mmol) in THF (4 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2.4 mmol) in THF (6 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 30 min. Then a solution of methyl 5-chloropyrazine-2-carboxylate (460 mg, 2.65 mmol) in THF (6 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane, then 0 to 5% methanol in dichloromethane) afforded the title compound (787 mg, 95%) as a white solid. MS: m/e=344.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][NH:23][CH2:24][C:25]#[N:26])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1.[CH:28](O)=[O:29].C(OC(=O)C)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][N:23]([CH2:24][C:25]#[N:26])[CH:28]=[O:29])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1
Reactant: O=CO
Reactant: N#CCNCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CCN(C=O)Cc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 0.376 g of [[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]-acetonitrile in 10 ml of tetrahydrofuran was treated with 0.1 ml of formic acid-acetic acid anhydride and the clear yellow solution which formed after a short time was stirred at room temperature for 45 minutes. After evaporation the residue was taken up in chloroform, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel with toluene/dioxane (9:1). N-[(10-Chloro-6,7-dihydro-4-oxo-3-phenyl-4H- benzo[a]quinolizine-1-yl)methyl]-N-(cyanomethyl)formamide formed a yellow resin.