Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH2:11][N:12]2[C:16]1[C:17]2[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][S:22][C:18]=2[N:19]=[CH:20][N:21]=1)(=O)=O.Cl.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][O:30]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(C(C)=O)C.C(Cl)Cl>[CH:25]([C:24]1[C:17]2[C:16]([N:12]3[CH2:11][CH:10]4[CH2:15][CH:13]3[CH2:14][CH:9]4[O:8][CH2:7][CH2:6][N:33]3[CH2:34][CH:29]4[CH2:35][CH:32]3[CH2:31][O:30]4)=[N:21][CH:20]=[N:19][C:18]=2[S:22][CH:23]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCOS(C)(=O)=O)c12
Reactant: C1OC2CNC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCN3CC4CC3CO4)c12
Temperature: 180 °C
Yield: 17.9 %

Procedure:
2-[[2-(5-Isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl methanesulfonate (0.11 g, 0.27 mmol), 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.072 g, 0.53 mmol) and potassium carbonate (0.11 g, 0.80 mmol) were combined in methyl ethyl ketone (2 mL)/DMF (1 mL, 12.8) and heated in the microwave for 30 minutes at 180° C. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by basic prep HPLC (method 2) to afford 5-[2-[[2-(5-isopropylthieno[2,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-5-yl]oxy]ethyl]-2-oxa-5-azabicyclo[2.2.1]heptane as a colourless gum (20 mg). LCMS RT=4.33 min. M+1=415.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:20]([OH:26])=[CH:19][CH:18]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:20]3[CH:19]=[CH:18][C:17]([CH3:16])=[C:25]4[C:21]=3[CH2:22][CH2:23][CH2:24]4)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Cc1ccc(O)c2c1CCC2
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: Cc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c2c1CCC2

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 7-methyl-indan-4-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10 g, 86% for the final step); LC-MS: 383 [M+1]+, tR=3.77 min. HPLC: 97.75% at 214 nm, 98.81% at 254 nm, tR=7.98 min. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=8.1 Hz), 6.77 (d, 1H, J=8.1 Hz), 5.88 (d, 1H, J=2.4 Hz), 5.49 (dd, 1H, J1=10.2 Hz, J2=4.8 Hz), 2.87 (t, 2H, J=7.5 Hz), 2.77 (t, 2H, J=7.5 Hz), 2.26 (s, 3H), 2.15˜2.07 (m, 2H), 1.80˜1.49 (m, 7H), 1.25˜1.14 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]([CH3:19])([CH2:16][CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:4][C:5]12[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:9](=[O:15])[NH:8][C:6]2=[O:7]
Reactant: CC(C)(CCO)CCC12C=CC=CC1C(=O)NC2=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)CCC12C=CC=CC1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.57 g (6.0 mmol) of 1-(3,3-dimethyl-5-hydroxypentyl)phthalimide and 0.92 ml (6.6 mmol) of triethylamine in 30 ml of dichloromethane was added, at 0C, 0.51 ml (6.6 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes at room temperature, to which was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane. The extract was dried, followed by distilling off the solvent to give 1-(3,3-dimethyl-5-methanesulfonyloxypentyl)phthalimide.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[C:1]([O-:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2)C1
Solvent: CC(C)=O
Product: O=C([O-])C(O)c1ccccc1
Product: O[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
In 66 ml of acetone were dissolved 17.7 g of dl-1-benzyl-3-hydroxypyrrolidine and 15.2 g of D-(-)-mandelic acid with heating and the solution was allowed to stand overnight at 4° C. to deposit crystals. Then, 8.5 g of the crystals thus deposited were collected and recrystallized from 26 ml of acetone to provide 5.1 g of D-(-) -mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine. The specific rotation [α]D20 was -45.5° C. (c=1, methanol). When the recrystallization was further repeated, the specific rotation was not changed. The melting point was 101°-102° C.
Reaction SMILES: [P:1]([O-])([O:5]CC)[O:2][CH2:3][CH3:4].O.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH2:3]([O:2][P:1]=[O:5])[CH3:4].[CH3:10][O:11][CH2:12][CH2:13][CH2:14][NH3+:15]
Reactant: COCCCN
Reactant: CCOP([O-])OCC
Solvent: CCO
Solvent: O
Product: CCOP=O
Product: COCCC[NH3+]
Yield: 94.3 %

Procedure:
A mixture of 13.81 g. of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 8.91 g. (0.1 moles) of 3-methoxypropyl amine and 30 ml. of ethanol as described in Example 1. 18.8 g. of 3-methoxypropyl-ammoniumethyl phosphanate are obtained. Yield: 94.3%. nD30 =1,4440
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C)c1
Yield: 55 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methylaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (26 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 41 mg (yield 55%) of the title compound.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH2:10]1[CH:14]2[CH2:15][C:16](=[O:17])[CH:12]([CH2:13]2)[CH2:11]1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>C(OCC)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:17][C:16]1[CH:12]2[CH2:13][CH:14]([CH:15]=1)[CH2:10][CH2:11]2
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CC2CCC1C2
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: C[Si](C)(C)OC1=CC2CCC1C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyllithium in diethyl ether (141 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g of diisopropylamine in 38 ml of dry diethyl ether. The resulting solution was cooled to -78° C. and 19.7 g of norcamphor in 20 ml of diethyl ether were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml of chlorotrimethylsilane were added. The reaction mixture was warmed to 25° C., stirred for 30 minutes, extracted with cold 5% aqueous sodium bicarbonate, dried (over MgSO4) and then distilled to give 22.3 g of 2-trimethylsiloxybicyclo[2.2.1]-hept-2-ene as a colorless liquid: bp 70°-73° C. (14 mm).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH2:14][OH:15])[NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCl.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:19][CH2:20][C:21]([N:10]1[CH:9]([CH2:14][OH:15])[CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC(CO)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1Cc2cc([N+](=O)[O-])ccc2CC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-methanol (1.648 g, 7.92 mmol), dichloromethane (60 ml) and triethylamine (1.1 ml), cooled in an ice bath, was added chloroacetyl chloride (0.651 ml). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with dilute hydrochloric acid and then with water. The organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to yield 2-chloro-1-(3-hydroxymethyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (2.08 g); MS 285 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH2:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][NH:41][C:42](=[O:69])[C@H:43]([N:51]1[CH2:56][C@@H:55]([CH2:57][C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]=2)[NH:54][CH2:53][C:52]1=[O:68])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C:2]([CH3:1])([CH3:9])[CH2:3]/[CH:4]=[CH:5]/[C:6]([N:54]1[CH2:53][C:52](=[O:68])[N:51]([C@@H:43]([C:42](=[O:69])[NH:41][CH3:40])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:56][C@H:55]1[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)=[O:8])([CH3:17])([CH3:16])[CH3:15]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)NCC1=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)N(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)CC1=O
Reaction time: 8 h

Procedure:
##STR102## (2E)-5-Methyl-5-(tert-butyloxycarbonylamino)hex-2-enoic acid was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazol (60 mg, 0.46 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (100 mg, 0.51 mmol) were added and the mixture was stirred for 15 min. (2R)-N-Methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide (185 mg, 0.46 mmol) and diisopropylethylamine (0.08 ml) were added and the mixture was stirred overnight. Water (10 ml) and methylene chloride (10 ml) were added and the mixture was washed with an aqueous solution of sodium hydrogen sulphate (10%, 20 ml), a saturated aqueous solution of sodium hydrogen carbonate (20 ml), dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 0.20 g of ((3E)-1,1-dimethyl-5-((2R)-4-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-((2-naphthyl)methyl)-5-oxopiperazin-1-yl)-5-oxopent-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: ClC1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:12][I:13].[C:14](#N)C>>[I-:13].[I:13][CH:12]1[C:11]2[N+:10]([CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: ClC1CCCc2cccnc21
Reactant: CC#N
Product: C[n+]1cccc2c1C(I)CCC2
Product: [I-]

Procedure:
A solution of 13.70 g of 5,6,7,8-tetrahydro-8-chloroquinoline (preparation given below), 86 ml of acetonitrile and 15.2 ml of methyl iodide was stirred for 68 hours at ambient temperature and crystallization was started after 50 minutes of reaction. The crystals were separated, rinsed with acetonitrile, then with ether and dried under reduced pressure at 20° C. to obtain 29.96 g of 8-iodo-1-methyl-5,6,7,8-tetrahydro-1-quinolinium iodide melting at 175° C.
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21]([C:23]2[C:24]3[CH:25]=[CH:26][NH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)=[O:22])(=O)=O)=CC=1.O.Cl>C(O)C>[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1)=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccc2NC(=O)c2cccc3[nH]ccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12

Procedure:
250 ml of a solution of potassium hydroxide in ethanol at 10 g per 100 ml were added to a suspension of 25 g of N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide in 50 ml of ethanol at 95° C. with stirring under an inert atmosphere and the mixture was stirred for 21 hours. 1 liter of iced water was added, and the mixture was acidified with a concentrated aqueous solution of hydrochloric acid, followed by stirring for a further 15 minutes, filtering, drying and triturating at reflux in 1.5 liters of methylene chloride. After concentrating to about 300 ml, filtering and drying at 80° C. under reduced pressure, 13 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide melting at ≃208° C. were obtained.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@@H:9]2[C:14]([OH:16])=O)[CH:2]=[CH2:3].[NH2:18][CH2:19][C:20]1[N:21]([O:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:22]=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:24](=[O:26])[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]([NH:18][CH2:19][C:20]1[N:21]([O:37][CH:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:22]=[C:23]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:24](=[O:26])[CH:25]=1)=[O:16])[CH:2]=[CH2:3]
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN)cc2=O)cc1
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
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=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)NCc1cc(=O)c(OCc2ccc(OC)cc2)cn1OC(c1ccccc1)c1ccccc1
Yield: 46.8 %

Procedure:
To a solution of (2R,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 32, 0.54 g, 2.27 mmol) in DMF (10 mL) at room temperature was added 2-(aminomethyl)-1-(benzhydryloxy)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one (Intermediate 293, 1 g, 2.27 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.724 g, 4.53 mmol) and N,N-diisopropylethylamine (1.579 mL, 9.07 mmol). After 15 minutes the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, and 1/1 brine/water twice. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-70% acetone/dichloromethane) afforded the title compound (0.704 g, 47%) as a light orange foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH:2]=[CH2:3].Cl.[CH3:15]N(C)CCCN=C=NCC.ON1[C:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:32]1[C@H:33]([CH3:15])[CH2:34][CH2:35][C@H:30]1[CH3:31])=[O:13])[CH:2]=[CH2:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: C=CCc1ccccc1CC(=O)O
Reactant: On1nnc2cccnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1ccccc1CC(=O)N1[C@H](C)CC[C@H]1C
Reaction time: 18 h
Yield: 378.2 %

Procedure:
To a solution of 2-allyl phenyl acetic acid (0.050 mg, 0.284 mmol) in Dimethylformamide (5 mL) was added 3-[3-(Dimethylamino)propyl]-1-ethylcarbodiimide hydrochloride (EDCI, 0.075 mmol, 0.397 mmol), 1-Hydroxy-7-azabenzotriazole (HOAt, 0.054 mg, 0.397 mmol), (2R,5R)-dimethylpyrrolidine (0.034 mL, 0.298 mmol) followed by triethylamine (0.118 mL, 0.851 mmol). The solution was stirred for 18 h and water was added (20 mL). The aqueous layer was extracted with diethylether and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (9/1 the 4/1) to give 2-(2-allyl-phenyl)-1-((2R,5R)-2,5-dimethyl-pyrrolidin-1-yl)-ethanone (colourless oil, 73 mg, 99%). C17H23NO; MW: 257.38; LCMS (method A) RT 1.84 min; ES 258 (100%, MH+), 280 (10%, MNa+); 1H NMR (400 MHz, CDCl3) δ 7.08-7.24 (4H, m), 5.97 (1H, m), 5.07 (1H, m), 4.99 (1H, m), 4.29 (1H, q), 4.01 (1H, q), 3.76 (1H, d), 3.58 (1H, d), 3.39 (2H, m), 2.08-2.26 (2H, m), 1.52-1.63 (2H, m), 1.23 (3H, d), 1.21 (3H, d) ppm.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:38])[N:26]([CH2:28][CH2:29][O:30]CC4C=CC=CC=4)[CH3:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:38])[N:26]([CH2:28][CH2:29][OH:30])[CH3:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(C(=O)N(C)CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(C(=O)N(C)CCO)cc3)cc3ccccc23)CC1
Yield: 72.2 %

Procedure:
Sequentially, the resulting 1-(4-ethylpiperazin-1-yl)-3-{4-(N-(2-benzyloxyethyl)-N-methylcarbamoyl]phenyl}isoquinoline (0.69 g) was converted into a hydrochloride in a conventional manner and then dissolved in methanol (50 ml). To the resulting solution was added 10% palladium/carbon catalyst (0.20 g), and the catalytic reduction was conducted at atmospheric pressure overnight. The catalyst was filtered off, while the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.41 g of the free compound of the title compound as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1)([F:12])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O.[OH-].[NH4+]>C(Cl)Cl>[CH3:33][S:34]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:14]=1)([F:1])[F:12])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCO)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOCC(F)(F)c1cccc(N2C(=O)CNC2=O)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Intermediate 62 (1.94 g, 5.45 mmol) was disolved in methylene chloride (15 mL) and triethylamine (1.21 mL, 8.72 mmol) was then added. The mixture was cooled to 0° C. and a solution of methanesulfonyl chloride (0.680 mL, 8.72 mmol) in methylene chloride (5 mL) was slowly added at the same temperature. The mixture was stirred at room temperature for 16 hours. The crude reaction was cooled to 0° C. and then 50% solution water/ammonium hydroxide (40 mL) was added. The organic layer was washed with water (2×40 mL), brine (1×40 mL), dried (Na2SO4) and concentrated. The title compound was obtained (2.4 g, 100%) as oil.
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[C@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (10.6 g, 65.6 mmol) were sequentially added to a solution of 2-chloro-N4-[(1S)-1-phenylethyl]quinoline-3,4-diamine (13.0 g, 43.7 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. for one hour. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added as heating at 90° C. was continued overnight. The reaction was still incomplete, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added in portions as heating at 90° C. was continued for a second night. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred for two hours. A precipitate was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 9.98 g of 4-chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: C(OC([C:11]1([NH2:32])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31])=O)C1C=CC=CC=1>[Pd].CO>[NH2:32][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31]
Reactant: CN1C(=O)C(N)(C(=O)OCc2ccccc2)N=C(c2ccccc2F)c2cc(Br)ccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reaction time: 21 h

Procedure:
A flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1 eg.; Example 8-D, Step A) and 10% palladium on carbon. Methanol was added, and the flask was placed under a balloon of H2. The reaction was stirred for 21 hours. The mixture was filtered through celite washing with methanol. The filtrate was concentrated to a white solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Product: COCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.33) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 57%). MS (ISP) 551.3 [(M+H)+]; mp 147–148° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(#N)N(C)C>[Br:20][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([N:3]([O:2][CH3:1])[CH3:19])=[O:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CON(C)C(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Yield: 78.3 %

Procedure:
4 g of N-methoxy-N-methyl-4'-methyl-4-biphenylcarboxamide, 3.34 g of N-bromosuccinimide and 0.02 g of azaisobutyronitrile in 50 mL of carbon tetrachloride were heated to boiling under reflux for 18 hours. The reaction mixture was diluted with 50 mL of methylene chloride and washed twice with 50 mL of water each time and once with 50 mL of saturated sodium chloride solution. The organic phases were dried over magnesium sulphate and concentrated. The residue was recrystallized from ethyl acetate. There was obtained 4.1 g (78%) of 4'-bromomethyl-N-methoxy-N-methyl-4-biphenylcarboxamide as a solid with a m.p. of 105°-106° C.