Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15]>CN(C)C=O.O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15])#[N:2]
Reactant: [C-]#N
Reactant: O=C1c2ccc(Cl)cc2CC1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1Cc2cc(Cl)ccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.4 g of sodium cyanide were dissolved in a mixture of 100 ml of dimethylformamide and 6 ml of water and initially charged. This solution was heated with stirring to 50° C., and 20.4 g of 2,5-dichloroindan-1-one, dissolved in 100 ml of dimethylformamide, were then added dropwise over a period of 60 minutes. After the addition had ended, stirring was continued at 50° C. for 1 hour. The mixture was then allowed to cool to room temperature and the solvent was stripped off using a rotary evaporator. The resulting crystal slurry was mixed with 200 ml of water and acidified to pH 4.5 using 10% by weight strength aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water, recrystallized from toluene and dried in a vacuum drying cabinet. This gave 18.5 g of 2-cyano-5-chloroindan-1-one (yield: 97% of theory).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][C:33]=4[CH3:41])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:17]=2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:2][C:3]#[CH:4].Cl.[N:43]([CH2:46][CH2:47][CH2:48][NH:49][CH3:50])=[N+:44]=[N-:45].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:43]([CH2:46][CH2:47][CH2:48][N:49]([CH3:50])[C:36](=[O:38])[C:35]1[CH:39]=[CH:40][C:32]([CH2:31][CH2:30][S:27]([N:24]2[CH2:23][CH2:22][C:18]3([N:17]=[C:16]([C:8]4[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([O:5][CH2:1][CH2:2][C:3]#[CH:4])[CH:7]=4)[NH:20][C:19]3=[O:21])[CH2:26][CH2:25]2)(=[O:28])=[O:29])=[C:33]([CH3:41])[CH:34]=1)=[N+:44]=[N-:45]
Reactant: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Reactant: CNCCCN=[N+]=[N-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)N(C)CCCN=[N+]=[N-])cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{2-[2-(3-But-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid, (3-azido-propyl)-methyl-amine hydrochloride (15.3 mg, 0.101 mmol) and DIPEA (0.044 ml, 0.255 mmol) were dissolved in DMF (0.400 ml). HATU (0.038 mg, 0.101 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with ethyl acetate, and the organic layer was then washed with a 1 M aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution and saline. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane-ethyl acetate) to give N-(3-azido-propyl)-4-{2-[2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,N-dimethyl-benzamide as a colorless oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:13][C:14]1[S:18][C:17]([C:19]([N:21]2[CH2:29][C:25]3([CH2:28][NH:27][CH2:26]3)[O:24][CH2:23][CH2:22]2)=[O:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:27]1[CH2:26][C:25]2([CH2:29][N:21]([C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[CH2:22][CH2:23][O:24]2)[CH2:28]1
Reactant: Cc1ccc(C(=O)N2CCOC3(CNC3)C2)s1
Reactant: OCCc1cccc(CBr)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCOC3(CN(Cc4cccc(CCO)c4)C3)C2)s1

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.281 g) was added to a solution of (5-methylthiophen-2-yl)(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)methanone hydrochloride (example 33, step h) (0.29 g) and triethylamine (0.42 mL) in acetonitrile (15 mL) at 20° C. and the resultant mixture stirred for 3 hours at 20° C. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.32 g.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Reaction time: 2 h

Procedure:
A solution of crude 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one in acetic acid (50 ml) and water (15 ml) was stirred at 45° C. for 2 hours and then at 65° C. for 2 hours. After evaporation of the solvent the residue was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted three times with methylene chloride. The organic layer combined was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (10% methanol-methylene chloride) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.0 g) as crystals.
Reaction SMILES: C(OP([CH2:8][C:9]([O:11]CC)=[O:10])OCC)C.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([C:22](=O)[CH3:23])[S:20][CH:21]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:22]([CH3:23])=[CH:8][C:9]([OH:11])=[O:10])[S:20][CH:21]=1
Reactant: CC(=O)c1cc(Br)cs1
Reactant: CCOC(=O)CP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of ethyl (diethoxyphosphino)acetate (34 mL, 171 mmol) in THF (35 mL) was added dropwise via addition funnel, over 20 minutes, to a 0° C. suspension of NaH (6.9 g, 60% oil dispersion, 172 mmol) in THF (200 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then treated with a solution of 1-(4-bromo-2-thienyl)ethanone (23.6 g, 115 mmol) in THF (75 mL). The reaction was warmed to room temperature, stirred for 4 hours, quenched with water, neutralized with 2N HCl, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in ethanol (350 mL) and THF (190 mL), treated with 2N LiOH (115 mL), stirred overnight at room temperature, and concentrated. The remaining aqueous solution was washed with diethyl ether, acidified with 2N HCl, and filtered. The filter cake was washed with water and dried to provide 22.38 g (79% yield) of the desired product as a mixture of E and Z isomers. MS (ESI(+)) m/e 244.7, 246.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][C:35]([OH:37])=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH2:34][C:35]([OH:37])=[O:36])[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC(=O)O
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-aminoyacetic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methylamino-acetic acid following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[ClH:1].[C:8]1([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cc(C2=CCCC2)nc2c1CCC2
Product: Cl
Product: OCCc1ccc(Nc2cc(C3=CCCC3)nc3c2CCC3)cc1
Yield: 71.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.095 g, 0.43 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.089 g, 0.65 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.110 g, 79%) as a yellow solid. MW=356.89. 1H NMR (DMSO-d6, 500 MHz) δ 13.67 (s, 1H), 9.71 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 6.99 (s, 1H), 6.66 (s, 1H), 3.64 (t, J=7.0 Hz, 2H), 3.13 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.56 (t, J=7.5 Hz, 4H), 2.18 (quin, J=7.5 Hz, 2H) 1.94 (quin, J=7.5 Hz, 2H); APCI MS m/z 321 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C#N)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[I:22]Cl>>[I:22][C:15]1[N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[N:17][CH:16]=1
Reactant: ClI
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Product: FC(F)(F)c1ccc(-c2ccc3ncc(I)n3c2)cc1
Yield: 67 %

Procedure:
Prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24 step 1) (2.3 g, 9 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light yellow solid (2.3 g, 67%). MS (ISP) 389.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[Cl:15]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[Cl:15]
Reactant: COC(=O)/C=C/c1sc2ccccc2c1Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1sc2ccccc2c1Cl
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A solution of 3.60 g (14.6 mmol) of 14 in 50 mL THF was treated with Wilkinson's catalyst (3.35 g, 3.62 mmol). The mixture was stirred under 1 atm H2 for 18 h and then was filtered through celite. The solvent was evaporated and the residue purified by flash chromatography on silica gel (0-2% ethyl acetate/hexane) to give 3.63 g (14.3 mmol, 99%) of the saturated ester (15).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.OO.[OH2:15].C(Cl)(Cl)Cl.C(O)(=[O:22])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])(=[O:22])=[O:15])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O
Reactant: ClCCCSc1ccc(Cl)cc1
Agent: OO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(CCCCl)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 58.50 g (0.266 mol) of 1-chloro-4-[(3-chloropropyl)thio]benzene in 125 mL of glacial acetic acid cooled in an ice bath was added 69 g of 30% H2O2 (0.609 mol). The mixture was stirred for 0.5 hr at ice bath temperature and then stirred at ambient temperature for 24 hr. The mixture was then heated at 80° C. for 20 hr. The reaction mixture was generated by addition of water (300 mL) and chloroform (300 mL). The mixture was stirred for 10 minutes and the phases separated. The organic layer was washed with an aqueous solution of sodium sulfite and then with aqueous 1M NaOH solution. The organic solution was dried (MgSO4) and concentrated to give a white solid. The solid was recrystallized from chloroform-ether at freezer temperature to obtain 57.74 g (86%), mp 72.5-73.5. The filtrate was concentrated to an oil which was triturated with ether and chilled in a freezer to obtain a second crop of 4.53 g (6.8%), mp 69°-72° C. The total yield was 62.27 g (92.8%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][S:10](=[S:13])([O-:12])=[O:11].[Na+].CN(C=O)C>O>[CH3:9][S:10](=[S:13])([O:12][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:11]
Reactant: BrCC1CCCCC1
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=S)OCC1CCCCC1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
The reaction mixture of bromomethylcyclohexane (1.560 g, 0.00881 mol), sodium methanethiosulfonate (1.180 g, 0.00881 mol) and dry DMF (6 mL) was heated at 50° C. for 24 hr. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a colorless oil (1.5033 g, 82%). IR (CDCl3 cast): 3030 (w), 3012 (w), 2926 (st), 2853 (st), 1446 (m), 1410 (m), 1320 (st), 1134 (st), 955 (st), 746 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.32 (s, 3H, CH3SO2S), 3.07 (d, J=6.9 Hz, 2H, SCH2CH), 1.95-1.55 (m, 6H), 1.40-0.90 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 50.42, 43.30, 37.83, 32.43, 26.02, 25.82.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]I)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:4]2[CH2:5][CH2:6][C:7](=[O:8])[CH:2]([F:1])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: O=C1CCNCC1F
Reactant: Clc1ccc(-c2ccccc2CI)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
3-Fluoro-piperidin-4-one (0.32 g, 2.7 mmol) was dissolved in DMF (13 mL) and 4′-chloro-2-(iodomethyl)biphenyl (1.03 g, 3.13 mmol) was added followed by DIPEA (1.06 g, 8.2 mmol). The reaction was stirred at ambient temperature for 16 hours, and then poured into EtOAc (100 mL). The organics were washed with water followed by brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel afforded the title compound (0.75 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.59 (m, 1H), 7.21-7.47 (m, 7H), 4.72-5.00 (m, 1H), 3.62-3.65 (d, J=12 Hz, 1H), 3.56-3.59 (d, J=12 Hz, 1H), 3.25-3.42 (m, 1H), 2.88-3.06 (m, 1H), 2.28-2.63 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:10][C:4]1([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]([CH3:1])([CH3:32])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(O)CC2(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88 %

Procedure:
A flask was charged with 1.5 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (3.33 mmol, 1.0 equiv). The ketone was dissolved in 16 mL of nitrogen-sparged tetrahydrofuran and cooled in an ice water bath. A solution of lithium aluminum hydride (3.33 mL, 6.66 mmol, 2 equiv, 2 M in THF) was added dropwise over 3 minutes to the solution. The solution was warmed to room temperature and stirred for 7 hours. The reaction mixture was quenched by the slow addition of aqueous hydrochloric acid (50 mL, 1 M). The solution was stirred vigorously until homogeneous. The phases were partitioned and the aqueous layer was collected. The aqueous layer was washed with ethyl acetate (4×20 mL), then the combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The resulting white solid was purified by column chromatography using an Isco CombiFlash Companion® with a Teledyne Isco RediSepRf column (40-g, flow rate: 40 mL/minute, gradient: 1 column volumes heptane, ramp up to 60:40 heptane:ethyl acetate over 7 column volumes, hold at 60:40 for 2 column volumes). The title compound was isolated as a white solid (1.32 g, 95 area % by HPLC at 254 nm, 88% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.81 (m, 1H), 7.40-7.28 (m, 2H), 7.23-7.17 (m, 1H), 7.00 (s, 2H), 4.04 (tt, J=10.2, 3.5 Hz, 1H), 2.94 (hept, J=6.9 Hz, 1H), 2.50 (hept, J=6.7 Hz, 2H), 1.92-1.74 (m, 2H), 1.71-1.57 (m, 2H), 1.38 (d, J=3.8 Hz, 6H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.8 Hz, 6H), 1.04 (s, 3H), 0.99 (s, 3H), 0.95 (d, J=6.7 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ=149.4 (d, J=36 Hz), 147.1, 145.5, 136.8 (d, J=6 Hz), 135.7 (d, J=3 Hz), 133.5 (d, J=32 Hz), 132.7 (d, J=7 Hz), 127.8, 125.0, 120.0, 66.4, 51.1 (d, J=12 Hz), 34.2, 33.7, 33.4 (d, J=4 Hz), 33.2, 30.8, 27.8 (d, J=4 Hz), 26.5, 24.3, 23.1. 31P NMR (CDCl3, 202 MHz) δ ppm 0.0.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:48])[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[F:45])[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][C:11]([F:47])([F:46])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:30][C:29]1[S:28][C:27]([C:38]2[C:39]([F:45])=[CH:40][CH:41]=[CH:42][C:43]=2[F:44])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][C:9]([NH2:8])([CH3:48])[CH2:10][C:11]([F:46])([F:47])[CH2:12]1)=[O:24]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(C)(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(C)(N)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
To a solution of tert-butyl N-(4-((5-(5-(tert-butoxycarbonylamino)-3,3-difluoro-5-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (0.36 g, 0.51 mmol) in MeOH (5 mL) was added HCl in dioxane (4 M, 0.02 mol, 5 mL). The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Purification via SCX cartridge washing with 1/1 MeOH/DCM (250 mL) followed by MeOH (250 mL) and eluting with 1 N NH3 in MeOH (200 mL) gave 495 as a pale yellow foam (250 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.85 (s, 1H), 7.33 (tt, J=8.4, 6.1 Hz, 1H), 7.07-6.99 (m, 2H), 6.28-6.06 (m, 2H), 3.78-3.74 (m, 3H), 3.65-3.40 (m, 3H), 3.29-3.20 (m, 1H), 2.41-2.16 (m, 2H), 1.96-1.85 (m, 1H), 1.77 (dt, J=14.7, 4.6 Hz, 1H), 1.26 (s, 3H). Exchangeables not observed. LCMS (ES+) m/z 498 (M+1)
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10][N:9]2C(=N[CH2:6][CH2:7][CH2:8]2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl.ClCC1C=NC=CC=1>C1C=CC=CC=1.C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH:26]([CH2:1][C:11]3[CH:10]=[N:9][CH:8]=[CH:7][CH:6]=3)[C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Agent: ClCc1cccnc1
Solvent: c1ccccc1
Solvent: CC#N
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3cccnc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.7 %

Procedure:
DBU (55 ul, 0.367 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (58.6 mg, 0.167 mmol) in benzene (16.0 ml) and acetonitrile (3 ml), under an atmosphere of argon. 3-(chloromethyl)pyridine hydrochloride (27.4 mg, 0.167 mmol) was then added. The reaction mixture was stirred at room temperature for 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (8.60 mg). 1H NMR (CDCl3): δ 1.40-1.80 (bm, 8H), 1.90 (m, 2H), 2.30 (m, 1H), 2.51 (m, 3H), 2.74 (d, J=17.27 Hz, 1H), 3.74 (m, 3H), 3.85 (s, 3H), 6.73 (d, J=8.32 Hz, 1H), 6.89 (m, 1H), 7.02 (s, 1H), 7.30 (m, 1H), 7.92 (m, 1H), 8.26 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=2[CH2:11][CH2:10]1.[Cl:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH3:37]>>[ClH:25].[CH3:37][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:12]=2[CH2:11][CH2:10]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC1CCCCN1)CC2
Reactant: Cc1ccc2ccccc2c1CCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCC1CCCCN1Cc1c(C)ccc3ccccc13)CC2
Product: Cl

Procedure:
Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.CC1O[N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[N:8]=1>CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])(=[NH:8])[NH2:10]
Reactant: COC(=O)c1cccc(-c2noc(C)n2)c1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C(=N)N)c1
Reaction time: 18 h

Procedure:
150 ml of acetic acid, 150 ml of water and 50 g of water-moist Raney nickel are added to a solution of 327 g (1.47 mol) of methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate in 3 l of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 18 hours. The catalyst is filtered off, and the filtrate is evaporated. The residue is taken up in tert-butyl methyl ether, heated to the boil and filtered off with suction. The residue is dried in vacuo: 3-methoxycarbonylbenzamidinium acetate as colourless crystals; m.p. 222°; ESI 179 (M+H); HPLC: Rt.=1.40 min (method A).