Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](SC)=[NH:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]([NH:30][NH2:31])=O)[CH:22]=2)[NH:17]1.O>CS(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[CH2:10][C:11]1[NH:12][C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:15])[CH2:25][CH2:24]3)=[N:30][N:31]=1
Reactant: CSC(=N)Cc1ccc(Cl)c(Cl)c1
Reactant: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Agent: I
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCc3nnc(Cc4ccc(Cl)c(Cl)c4)[nH]3)ccc2N1
Temperature: 115 °C

Procedure:
To the stirred solution of methyl 2-(3,4-dichlorophenyl)ethanimidothioate hydroiodide (0.184 g, 0.51 mmol) in dry DMSO (1 mL) were added 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (0.120 g, 0.51 mmol) and TEA (0.103 g, 1.02 mmol) and heated at 115° C. in a seal tube overnight. Water was added to the reaction mixture. The solid precipate was filtered, dried and purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a gradient of ACN in 0.1% TFA (0-100%) to give 6-((5-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off white solid (0.070 g; 34%). 1HNMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 4.09 (s, 2H), 5.01 (s, 2H), 6.75-6.76 (m, 2H), 6.88 (s, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.59 (d, J=8.00 Hz, 2H), 9.91 (s, 1H), 13.87 (bs, 1H). LCMS: RT 1.71 min; LCMS (ES-API), m/z 403.0.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].F[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a mixture of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-4-one (100 mg, 0.19 mmol) (from Example 16, Step C) and sodium hydride (4.5 mg, 0.19 mmol) in DMF, (0.5 mL) which had been stirring at room temperature for 2 h, was added dropwise a solution of 4-fluoro-nitrobenzene (27 mg, 0.19 mmol) dissolved in 0.3 mL DMF. The yellow reaction mixture was stirred at 60° C. for 29 hours. After cooling to room temperature, water and EtOAc were added and the phases were separated. After two more extractions with EtOAc, the organic layers were combined and washed twice with water, and brine, and then dried over Na2SO4. The crude product obtained after filtration and evaporation of volatiles was flash chromatographed over silica gel (gradient elution using 0.3-5.0% MeOH/CH2Cl2) to afford 53 mg (43%) of the title compound as an off-white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 652 (M+1)+ ; mp 186°-187° C.
Reaction SMILES: [Br:1][C:2](=[CH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[OH-].[Na+].O.[CH:15]([Br:18])(Br)[Br:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]2([Br:1])[CH2:11][C:15]2([Br:18])[Br:16])=[CH:9][CH:8]=1
Reactant: C=C(Br)Cc1ccc(Cl)cc1
Reactant: BrC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc(CC2(Br)CC2(Br)Br)cc1
Temperature: 58.5 °C

Procedure:
To a solution of 11.4 g (0.0494 mol) of 1-(2-bromo-allyl)-4-chloro-benzene in 20 ml of bromoform was added 0.686 g (0.00213 mol) tetrabutylammonium bromide. After heating to 58.5° C. for an hour, 10.7 ml (0.0494 mol) of 50% aqueous sodium hydroxide was added. This was repeated seven times over two days. After cooling to room temperature there was added hexanes and water. This mixture was gravity filtered through qualitative fluted filter paper. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo. This residue was purified by column chromatography with hexanes to give 2.3 g of 2-(4-chlorophenylmethyl)-1,1,2-tribromocyclopropane.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:11]([N+:32]([O-:34])=[O:33])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[F:20])[N:16]([C@@H:22]1[CH2:24][C@@H:23]1[F:25])[CH:15]=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]2=[O:31].O.C(Cl)(Cl)Cl>CN(C)C=O>[F:20][C:19]1[C:18]([CH3:21])=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][N:16]2[C@@H:22]2[CH2:24][C@@H:23]2[F:25])=[C:11]([N+:32]([O-:34])=[O:33])[CH:10]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(N)c([N+](=O)[O-])c2c1=O
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc([N+](=O)[O-])c2c1=O
Temperature: 65 °C
Yield: 60.7 %

Procedure:
Isoamyl nitrite (2.56 ml, 19.1 mmol) was added to dimethylformamide (40 ml), and while stirring at 65° C., a solution, wherein ethyl 6-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate (5.00 g, 13.6 mmol) was dissolved in dimethylformamide (60 ml), was added dropwise over a period of 3 hours. After completion of dripping, the reaction solution was stirred at 65° C. for 4 hours, allowed to cool, and then poured into water (500 ml). After extraction with chloroform (200 ml×3), the organic layers combined were washed with 1 mol/l hydrochloric acid (200 ml) and saturated saline solution (100 ml×2) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and the residue obtained was applied to a silica gel chromatography to obtain 2.91 g (61%) of the title compound in the form of a white powder from a chloroform:methanol=30:1 eluate.
Reaction SMILES: [C:1](N1C=NC=N1)(N1C=NC=N1)=[O:2].[Br:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]1[N:21]=[C:22]([CH3:28])[N:23]([NH:25][CH:26]=[NH:27])[CH:24]=1>O1CCOCC1.CO>[Br:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]1[N:21]=[C:22]([CH3:28])[N:23]2[C:24]=1[C:1](=[O:2])[NH:27][CH:26]=[N:25]2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1NC=N
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1,1′-Carbonylbis(1H-1,2,4-triazole) (90%, 2.69 g, 14.8 mmol) and N-[4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-yl]imidoformamide (2.69 g, 9.50 mmol) were combined in 1,4-dioxane (63 mL) and the mixture was stirred for 3.5 hours at room temperature, then heated to 50° C. for 1 hour. Additional 1,1′-carbonylbis(1H-1,2,4-triazole) (90%, 1.34 g, 7.35 mmol) was added, and heating was continued for 30 minutes. After another addition of 1,1′-carbonylbis(1H-1,2,4-triazole) (90%, 269 mg, 1.48 mmol), heating at 50° C. was carried out for an additional 75 minutes. The reaction was allowed to cool to room temperature, and was then concentrated to half its original volume; the precipitate was collected and washed with ethyl acetate to afford a white solid. This was dissolved in methanol (50 mL), concentrated to dryness and triturated with water (25 mL). After collection of the solid, it was washed with 2-propanol followed by diethyl ether to provide C3 as a white solid. Yield: 1.95 g, 6.31 mmol, 66%. LCMS m/z 309.4 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.53 (s, 3H), 3.87 (s, 3H), 7.87 (s, 1H), 8.17 (s, 1H), 11.69 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[CH:20][N:19]=[CH:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4cnco4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(1,3-oxazol-5-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine. LCMS: purity: 76%; MS (m/e): 364 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[C:18](=S)=[S:19].[OH-].[Na+].C(Cl)(=O)OCC>O>[N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[C:18]=[S:19]
Reactant: S=C=S
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1ccc2cc(OCCCN=C=S)ccc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
1.28 g of 6-(3-aminopropoxy)carbostyril hydrochloride was added, at 0° C., to 10 ml of an aqueous solution containing 0.3 g of carbon disulfide and 0.4 g of sodium hydroxide. The mixture was stirred at 80° C. for about 2 hours. Thereto was added 0.55 g of ethyl chlorocarbonate at 35° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The filtrate was dried with magnesium sulfate. The solvent was removed by distillation. To the resulting residue was added diethyl ether, and the resulting crystals were collected by filtration and purified by a silica gel column chromatography (eluant: 3.3% methanol/dichloromethane) to obtain 0.22 g of 6-(3-isothiocyanatopropoxy)carbostyril.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5ccccc5c4)nc3s2)CC1
Yield: 46 %

Procedure:
5-Chloro-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (130 mg) was reacted with 92 mg of 3-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)quinoline via General Procedure A. The product was purified by reverse phase HPLC to yield 72.6 mg of 112. MS (Q1) 526.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>[Cl-].[Zn+2].[Cl-]>[C:10]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:9]
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(c1ccccc1)c1ccc(N)cc1
Yield: 78 %

Procedure:
18.6 Parts of aniline, 20.4 parts of 36% w/w hydrochloric acid containing 13.6 parts of zinc chloride are stirred and refluxed for 24 hours with 23.6 parts of α-methylstyrene. The work-up follows Example 3 and gives on distillation 32.9 parts of 4-cumylaniline mb4 175°-80° C. (78% yield based on a 93% purity by G.L.C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[C:11](=O)[CH:10]([CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:25]([N:32]1[C:11]2[CH:10]([CH3:24])[CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][C:12]=2[CH:14]=[C:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1CN(Cc2ccccc2)CC(CC(=O)c2ccccc2)C1=O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CN(Cc2ccccc2)Cc2cc(-c3ccccc3)n(Cc3ccccc3)c21
Yield: 84.4 %

Procedure:
A mixture of 1-benzyl-3-methyl-5-phenacyl-4-piperidone (3.2 g), benzylamine(1.1 g), p-toluenesulphonic acid (0.1 g) and dry toluene (100 ml) was heated under reflux under a Dean and Stark trap for 3 days. Removal of thesolvent left a yellow solid, which on recrystallisation from methanol gave 3.3 g of the product as pale yellow prisms. M.pt. 131° C (Found: C 85.2; H, 7.2; N, 7.1. C28H28N2 requires: C, 85.7; H, 7.2;N, 7.1%).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCC#CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC#CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Thereto, 2-octadecyn-1-ol (510 mg) was dissolved in dichloromethane (20 mL) and carbontetrabromide (960 mg) and triphenylphosphine (660 mg) were added at 0° C., followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate-99:1→95:5) to obtain the title compound (630 mg) having the following physical property values.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:14]([C:13]([F:12])([F:27])[F:28])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3,5-bis-trifluoromethyl-benzoyl chloride according to the procedure of Example 256a substituting 3,5-bis-trifluoromethyl-benzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3,5-bis-trifluoromethyl-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-3-methyl-butane (0.133 mL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-iso-pentyl-1H-pyrazole (115 mg, 59%) as a clear oil.
Reaction SMILES: [C:1]12([C:14]([O:16]C)=[O:15])[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO.O>[CH3:13][O:12][C:10]([C:5]12[CH2:6][CH2:7][C:1]([C:14]([OH:16])=[O:15])([CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4]2)=[O:11]
Reactant: COC(=O)C12CCCC(C(=O)OC)(CC1)CC2
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C12CCCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of dimethyl bicyclo[3.2.2]nonane-1,5-dicarboxylate (2.02 g, 8.41 mmol), in methanol (20 mL) and water (4 mL) was added barium hydroxide octahydrate (1.33 g, 4.20 mmol). The reaction mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and washed with isohexane (2×100 mL), then the aqueous phase was acidified with 2M HCl to pH 2 and extracted into EtOAc (2×100 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave the title compound (931 mg, 4.11 mmol, 49%) as a clear colourless gum which slowly formed a white solid; 1H NMR (CDCl3) δ 1.72-1.75 (m, 2H), 1.87-1.92 (m, 12H), 3.65 (s, 3H); GC-MS EI m/e M+ 226.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:30]([CH3:32])[CH3:31])=[N:13][C:14]2[C:15]([CH3:29])([CH3:28])[CH2:16][N:17]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=3)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(Cc1ccc(F)cc1)CC2(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
A mixture of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol) and 4-fluorobenzaldehyde (0.048 mL, 0.452 mmol) was stirred in CH2Cl2 (1 mL) at 0° C. for 45 min. AcOH (2.59 μl, 0.045 mmol) was added followed by NaBH(OAc)3 (9.58 mg, 0.045 mmol). After stirring at 0° C. for an additional 5 min, the reaction mixture was stirred at room temperature for 22 h. Additional NaBH(OAc)3 (9.58 mg, 0.045 mmol) and AcOH (2.59 μl, 0.045 mmol) were added and the mixture was stirred for an additional 1 h. The mixture was quenched with satd NaHCO3 and the product was extracted with CH2Cl2, dried (Na2SO4), filtered and adsorbed onto silica gel. The product was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-tert-butoxy-2-(6-(4-fluorobenzyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (14.7 mg, 47% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (ddd, J=2.14, 5.72, 8.32 Hz, 1H), 7.24-7.28 (m, 2H), 7.14-7.20 (m, 2H), 7.06-7.14 (m, 1H), 6.99 (t, J=8.70 Hz, 2H), 4.83 (s, 1H), 3.71 (s, 3H), 3.45-3.60 (m, 2H), 3.40 (d, J=13.43 Hz, 1H), 3.23 (d, J=15.26 Hz, 1H), 3.06 (d, J=15.26 Hz, 1H), 2.50 (d, J=10.99 Hz, 1H), 2.34 (d, J=11.29 Hz, 1H), 1.33 (d, J=2.44 Hz, 6H), 1.28 (s, 3H), 1.11 (d, J=6.71 Hz, 3H), 0.98 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −114.17, −116.52. LCMS (M+H) calcd for C33H41F2N2O3: 551.30. found: 551.4. By NMR.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)Nc4ccccc4)c3)ncnc12
Reaction time: 8 h
Yield: 34 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(3-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at it overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 413.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH2:35])[CH2:31][N:32]([CH3:34])[CH3:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH:35][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][N:32]([CH3:33])[CH3:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=361.5 ([M−H]−), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 9-phenylnonanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(9-phenyl-nonanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C([Li])CCC.[F:16][C:17]([F:21])=[C:18](F)[F:19].Cl>CCCCCC.C(OCC)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:18]([F:19])=[C:17]([F:21])[F:16])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(I)cc1
Reactant: FC(F)=C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCc1ccc(C(F)=C(F)F)cc1
Temperature: -80 °C
Yield: 59.9 %

Procedure:
In 1 l four-necked flask having a gas supplying tube, 200 ml of n-hexane, 75 ml of dry diethyl ether and 24.6 g (0.1 mol) of 4-(n-propyl)iodobenzene were introduced under a nitrogen atmosphere, and then 86.2 ml of a hexane solution of n-butyl lithium (1.16 mol) was dropwise added thereto under stirring at -80° C. Then, while the reaction system was maintained at -80° C., 10 g (0.1 mol) of tetrafluoroethylene was introduced under vigorously stirring in 30 minutes. The reaction solution was stirred further for one hour and poured into ice water and neutralized with dilute hydrochloric acid, and then the organic layer was separated. The aqueous layer was extracted with methylene chloride, and the extract was combined to the organic layer, followed by drying. The solvent was distilled off to obtain 12 g (yield: 60%) of 1-(4-n-propylphenyl)-1,2,2-trifluoroethylene.