Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].C(O)(=O)C.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[O:21]=[C:25]([CH2:24][C:23]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:22]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 6.2 g (50 mmoles) dimethyl methylphosphonate (Aldrich) in 125 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 21 ml of 2.37 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 7.5 g (50.0 mmole) methyl was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatonous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 134°-5° (<0.1 mm) to give 3.5 g (29%) dimethyl 2-oxo-3-phenylpropylphosphonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(COC)OC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: C1COCCN1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
4-(2-Nitro-4-trifluoromethylphenyl)morpholine was prepared by reaction of 4-chloro-3-nitrobenzotrifluoride with equimolar amounts of morpholine and triethylamine in monoglyme. The resultant product melts at 37°-39° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[N+:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([CH2:45][C:46](O)=[O:47])[C:38]2=[O:49])([O-:34])=[O:33]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:46](=[O:47])[CH2:45][N:39]1[C:38](=[O:49])[C:37]2[C:41](=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=2)[C:40]1=[O:44]
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol) was placed in a 50 ml round bottom flask and dissolved in DMF (3 ml), EDC (45.6 mg, 0.238 mmol), and 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetic acid (60 mg, 0.238 mmol) were added to it followed by DMAP (29.1 mg, 0.238 mmol). The reaction was stirred at RT for 6 hours. The reaction was quenched by adding 30 ml of HCl/H2O (1M) and extracted with EtOAc (30 ml). The organic phase (EtOAc) was extracted with HCl/H2O (1M; 30 ml; ×3) and subsequently with K2CO3/H2O (15% w/w; 20 ml; ×3) by using a 100 ml extracting funnel. The resulting organic extract was dried over Na2SO4 (0.5 g), filtered on a filter paper, and the solvent removed under reduced pressure. The oil residue was purified by preparative HPLC (Method 2) to yield 120 mg of desired product (yield=77%). 1H NMR (400 MHz, acetone) δ ppm 8.35 (d, J=7.50 Hz, 1H), 8.24-8.30 (m, 1H), 8.16-8.24 (m, 3H), 7.16-7.25 (m, 2H), 7.05 (dd, J=8.16, 1.98 Hz, 1H), 6.94 (t, 1H, CHF2), 6.14 (dd, J=9.48, 4.63 Hz, 1H), 4.52 (s, 2H), 4.01 (dd, J=6.62, 3.97 Hz, 2H), 3.54 (dd, J=14.33, 9.48 Hz, 1H), 3.26-3.40 (m, 1H), 1.25-1.38 (m, 1H), 0.56-0.73 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=652.1
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:12])=[O:11])[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:26]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [C:1]([C:3]1[CH:4]=C(C=CC=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38]>>[CH:4]1([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=4)[C:27]#[N:28])[N:18]=3)[CH:13]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:12]2=[O:38])[CH2:3][CH2:1]1
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(Nc2nccc(N3CCN(CC4CC4)C(=O)C3c3ccccc3)n2)c1
Yield: 72 %

Procedure:
Intermediate 4, (0.20 g, 0.58 mmol) and 3-cyanoaniline (0.14 g, 1.17 mmol) were reacted together following the procedure detailed for the compound of Example 2 which gave the title compound as a pale yellow solid (0.18 g, 72%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7](Cl)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[NH:18]1[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1.F[C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)[CH2:19]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Na2CO3 (7.81 g, 73.7 mmol) then CbzCl (6.88 mL, 48.2 mmol) was added to a solution of 399 (10.28 g, 39.2 mmol) (399 was synthesized following the procedure J starting from (R)-pyrrolidin-3-amine and tert-butyl 4-fluorobenzoate) in DCM (196 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. It was then quenched with saturated NH4Cl, stirred for 30 min, diluted with DCM, washed with brine then H2O, dried with MgSO4, filtered and concentrated to afford the title compound 400 (16.4 g, quant.) as a beige solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=2)([C:22]#[N:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]([C:22]#[N:23])([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(CCl)c2)CC1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(COCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Sodium hydride (60% oil suspension, 191 mg, 4.77 mmol) was added to a solution of 2,2,2-trifluoro-ethanol (347 μl, 4.77 mmol) and 4-(3-chloromethyl-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (600 mg, 1.59 mmol) in DMF (8 ml) at 0° C. The mixture was stirred at room temperature overnight, and then quenched with water and diluted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous NaHCO3 solution, water (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→1/2) to give 4-cyano-4-[3-(2,2,2-trifluoro-ethoxymethyl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (366 mg, 52%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:2]1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:2]1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccccc23)cc1
Reaction time: 0.25 h

Procedure:
A solution of methyl 4-((1H-indol-3-yl)methyl)benzoate (0.250 g, 0.94 mmol) in THF is added dropwise to a suspension of NaH (0.048 g, 1.19 mmol) in THF. The mixture is stirred for 15 minutes, treated with methyl iodide (0.154 g, 1.08 mmol), stirred for 30 minutes and concentrated in vacuo. The resultant solid residue is partioned between CH2Cl2 and H2O. The organic phase is separated, dried over Na2SO4 and concentrated to dryness to yield methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1.[Fe]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)cc(N)c1SCc1ccccc1

Procedure:
17.7 g of iron turnings are heated to 66° C. in 80 ml of acetic acid (5%) with thorough stirring. A solution of 12.0 g (0.034 mol) of 2-benzylthio-3,5-dinitrobenzoic acid methyl ester in 20 ml of tetrahydrofuran is then slowly added dropwise. After cooling, the batch is neutralised with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated. Crystallisation from diethyl ether gives 8.1 g (82% of the theoretical yield) of product; m.p. 80°-82° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 73 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-tert-butylbenzoyl chloride (0.244 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.47 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-tert-butylbenzamide (0.221 g, 73% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=6.6 Hz, 2H), δ 7.43 (d, J=9.0 Hz, 2H), δ 6.95 (t, J=3.9 Hz, 1H), δ 3.59 (q, J=5.4, 5.7 Hz, 2H), δ 3.50 (t, J=5.1 Hz, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.4, 131.4, 127.2, 125.8, 51.1, 39.7, 35.2, 31.4 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1480. found 246.1479.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:2].Br[C:17]1[CH:22]=[CH:21][N:20]=[N:19][CH:18]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[N:19]1[CH:18]=[CH:17][C:22]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=2)=[CH:21][N:20]=1
Reactant: Brc1ccnnc1
Reactant: CCOC(=O)Cc1ccc(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: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 4-(2-ethoxy-2-oxoethyl)phenylboronic acid 37-2 (310 mg, 1.5 mmol), 4-bromopyridazine 37-1 (158 mg, 1 mmol), Pd(PPh3)4 (70 mg, 0.1 mmol), toluene (4 mL), ethanol (1 mL) and 2M Na2CO3 (1.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution and brine. The organic phase was dried over Na2SO4 and then concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 as pale yellow solid. MS m/z 243.1 (M+1)
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])[CH2:21]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1ccccc1C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(2-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 12.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 29 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.CO>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:3]([O:1][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Yield: 95 %

Procedure:
Compound 11 (Rb═H, 0.84 g, 2.66 mmol) was dissolved in DCM/water, 2/1, v/v (30 ml) and to this solution was added sodium hydroxide (2N, 4.2 ml). To this mixture was added tetrabutyl-ammonium bromide (0.09 g, 0.27 mmol, 0.1 eq) and benzyl bromide (0.35 ml, 2.93 mmol, 1.1 eg). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis (DCM/MeOH, 98/2, v/v, Rf 0.8) showed complete reaction. The mixture was diluted with DCM (100 ml), the layers were separated and the water layer was extracted with DCM. The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/petroleum ether, 3/1 to 1/0, v/v) to give compound 12 (Ra═Rb═H, 1.03 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H); 2.75 (bs, 2H); 3.75 (bs, 2H); 4.35 (bs, 2H); 5.05 (s, 2H); 6.35 (s, 1H); 6.98 (d, 2H); 7.30-7.55 (m, 7H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CCN(CC)CC.[CH2:17]([O:19][C:20](=[O:31])[CH:21]([C:28](Cl)=[O:29])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:31])[CH:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:29])[CH3:18]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(=O)C(C(=O)Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25 %

Procedure:
A solution of 2-cyclohexyl-malonic acid monoethyl ester (2.9 g, 14 mmol; CAS Reg. No. 147596-63-2) in thionyl chloride (29 ml) was heated under reflux conditions for 2 h. The solvent was removed under reduced pressure to give chlorocarbonyl-cyclohexyl-acetic acid ethyl ester. 1,2,3-Benzotriazole (1.47 g, 12 mmol) was dissolved at ambient temperature under an argon atmosphere in CH2Cl2 (45 ml). Et3N (1.86 ml, 13 mmol) and a solution of chlorocarbonyl-cyclohexyl-acetic acid ethyl ester in CH2Cl2 (4 ml) was added. The reaction mixture was stirred at ambient temperature for 14 h, quenched with ice cold aqueous 2 N HCl and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.05 g, 3.3 mmol; 25%) as yellow oil. MS: m/e=316.2 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([OH:9])[C:4](=[NH:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>CS(C)=O>[NH:10]=[C:4]1[N:3]=[C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([CH3:8])[N:5]1[OH:9]
Reactant: C1CSCCN1
Reactant: Cc1cc(Cl)nc(=N)n1O
Solvent: CS(C)=O
Product: Cc1cc(N2CCSCC2)nc(=N)n1O
Temperature: 100 °C
Yield: 50.7 %

Procedure:
A mixture of 32 g of 4-chloro-1,2-dihydro-2-imino-6-methyl-1-pyrimidinol, 46 g of thiomorphline, and 200 ml of dimethyl sulfoxide was heated at 100°C in a nitrogen atmosphere for 17 hours. The solvent is removed under high vacuum. The residue is shaken with 5% ammonium hydroxide solution and with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent removed. Trituration of the residue with ether gives 23 g of a solid mp 208°-210°C. Recrystallization from acetone-methanol gives a white crystalline solid, mp 243°-245°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in N,N-dimethylformamide (1 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid prepared according to the same procedures as preparation 14 (18 mg) and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (33 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2C=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:32]3[CH2:38][CH2:39][CH2:40][CH2:35][CH2:36]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].[CH2:33](Br)[CH:34]=[CH2:35].C(N=C(SCC=C)NC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)(OC)=O>CC(C)=O.O>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH2:35][CH:34]=[CH2:33])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Reactant: C=CCBr
Agent: C=CCSC(=NC(=O)OC)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C=CCSC(=NC(=O)OC)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone (2.09 g.; 0.005 mole) in acetone (40 ml.) and water (6.0 ml.) is added an aqueous sodium hydroxide solution (50% aqueous; 0.4 g.). The suspension is stirred at room temperature for one hour and then allyl bromide (0.6 g.; 0.005 mole) is added and the solution is stirred at room temperature over the weekend. The precipitate which forms is collected by filtration and then dried to afford 1.3 g. of 3-iminophenylmethyl)-4-(3-carbomethoxy-S-allylisothioureido)benzophenone, m.p. 125°-127° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and 2-amino-2-ethyl-N-methyl-butyramide (78.2 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 9.44%) as colorless sticky solid, LC-MS (UV peak area, ESI) 97.47%, 361.4 (M+H).