Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:37][C:34]1[CH:33]=[C:32]([Cl:38])[CH:31]=[CH:36][C:35]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][C@@H:10]([CH3:21])[C@H:9]([OH:8])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccc(Br)c(Cl)c1
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: C[C@H](Oc1ccc(-c2ccc(Cl)cc2Cl)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 1-bromo-2,4-dichlorobenzene (0.218 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g)in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with sodium hydrogen carbonate solution (in water) and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a solid (0.064 g) from which the oxalate salt was prepared (0.054 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1.S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1ccc(CO)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of 10.5 g of ethyl 6-hydroxymethylnicotinate in chloroform (100 ml) was cooled to 0° C., and 8.28 g of thionyl chloride was added dropwise to the solution. The mixture was stirred at 0° C. for 2 hours, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexene/ethyl acetate=6/1) to obtain 10.52 g of ethyl 6-chloromethylnicotinate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([F:18])[C:10]=2[F:19])[CH:7]=1.[Li][CH2:22]CCC.CCCCCC.C[Si](C)(C)[O:34][C@@H:35]1[C@@H:40]([O:41][Si](C)(C)C)[C@H:39]([O:46][Si](C)(C)C)[C@@H:38]([CH2:51][O:52][Si](C)(C)C)[O:37][C:36]1=[O:57].CS(O)(=O)=O>C1COCC1.CO>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([C@@:36]2([O:57][CH3:22])[C@H:35]([OH:34])[C@@H:40]([OH:41])[C@H:39]([OH:46])[C@@H:38]([CH2:51][OH:52])[O:37]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([F:18])[C:10]=1[F:19]
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[(5-bromo-2-chloro-phenyl)methyl]-4-ethoxy-2,3-difluoro-benzene 3e (5.5 g, 15.3 mmol) was dissolved in 20 mL THF and cooled to −78° C., followed by dropwise addition of a solution of n-BuLi in n-hexane (7.3 mL, 18.3 mmol). The reaction mixture was stirred for 1 hour at −78° C. 30 mL solution of (3R,4S,5R,6R)-3,4,5-tris (trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (7.5 g, 16.1 mmol) in THF at −78° C. were added before the reaction mixture was stirred for 2 hours at −78° C. A solution (51 mL) of 0.6 M methanesulfonic acid in methanol was added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure, dissolved in water (50 mL) and extracted with ethyl acetate (100 mL×4). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 3f (3.05 g, white solid), yield: 45.5%.
Reaction SMILES: C([O:3][C:4]([C:6]1([F:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.[NH3:20]>CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([C:4](=[O:3])[NH2:20])([F:19])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Fluoro-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.8 mmol, 0.5 g) was taken in 7M NH3 in MeOH (5 mL) and stirred at room temperature for 12 h in a sealed vial. All volatiles were removed under reduced pressure to provide 4-carbamoyl-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester as white solid.
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[Si](C#N)(C)C>C(N(CC)CC)C>[F:4][C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:1]#[N:3])[CH:7]=1
Reactant: FC(F)(F)c1ccncc1
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 70 ml of acetonitrile were added 6 g of 4-trifluoromethylpyridine=N-oxide, 10.26 ml of triethylamine, and 10.95 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.5 g of 4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][S:11][C:10]=2[CH:13]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: CCNCCOC
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Product: CCN(CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and N-(Methoxyethyl)ethylamine were converted to yield Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-amine as light brown oil, MS: 396 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH:17](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(#N)C>[CH3:17][O:1][C:2]1[C:10](=[O:11])[N:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C1=C(O)C(=O)N2CCCCC12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)C1=C(OC)C(=O)N2CCCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
At 0° C. to a solution of Intermediate 22C (30 mg, 0.13 mmol) and N,N-diisopropylethylamine (35 μL, 0.20 mmol) in methanol (0.15 mL) and acetonitrile (1.35 mL) was added (trimethylsilyl)diazomethane (0.10 mL, 2.0 M in diethyl ether, 0.20 mmol). The reaction mixture was stirred at rt for 2 h, concentrated and the residue was purified by ISCO chromatography (ethyl acetate/hexane 0-100%, column, 4 g) to afford Intermediate 22D (20 mg, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25-1.41 (5H, m), 1.50-1.61 (1H, m), 1.76-1.98 (2H, m), 2.44-2.52 (1H, m), 2.79-2.90 (1H, m), 3.95 (1H, dd, J=11.4, 3.6 Hz), 4.23-4.38 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[N:8]=[CH:7][C:6]([C:23]#[N:24])=[C:5]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=2)=[C:28]([Cl:39])[CH:27]=1.C=O.[C:42]([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[Cl:39][C:28]1[CH:27]=[C:26]([NH:25][C:5]2[C:4]3[C:9](=[CH:10][C:11]([N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[CH2:19][CH2:20][CH2:21][CH2:22]5)[CH2:16][CH2:17]4)=[C:2]([NH:1][CH3:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:23]#[N:24])[CH:31]=[CH:30][C:29]=1[S:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A mixture of 130 mg (0.23 mmol) of 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile, 12.0 mg (0.4 mmol) of paraformaldehyde, 25.0 mg (0.39 mmol) of sodium cyanoborohydride and 2 drops of acetic acid in 15 mL of ethanol is heated under reflux for 8 hours. The mixture is cooled to room temperature and solvent removed in vacuo. A 12 mL solution of 1N sodium hydroxide is added to the residue, and the mixture is stirred. A crude solid is collected by filtration, washed with water and dried. Purification by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 66.0 mg of the 4-({3-Chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-(methylamino)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as an yellow solid, mp 242-250° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30]([O-])=[O:31])[C:25]([O:27][CH3:28])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30](=[O:31])[N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:5][CH2:6]1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.65 g (4.84 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to a mixture of 1.19 g (4.85 mmol) 1-methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-succinate, 1.56 g (4.85 mmol) TBTU, 0.73 mL (5.00 mmol) triethylamine, in 30 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was taken up in 200 mL EtOAc, the organic phase was washed with 10% citric acid and saturated Na2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O=[C:24]([CH2:28][CH3:29])[C:25]([OH:27])=[O:26]>C(O)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[N:6]=[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([C:12]([F:22])([F:21])[F:11])[CH:14]=1)[C:28]([CH3:29])=[C:24]2[C:25]([OH:27])=[O:26]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1cc(N)ccc1F
Reactant: CCC(=O)C(=O)O
Solvent: CCO
Product: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 4-fluoro-3-(methyloxy)aniline (13.6 g, 96 mmol) and 3-(trifluoromethyl)benzaldehyde (16.78 g, 96 mmol) in ethanol (200 mL) was heated to reflux for 1 h. 2-Oxobutanoic acid (9.84 g, 96 mmol) was added portionwise. The reaction mixture was stirred at reflux for an additional 3 h, cooled to room temperature, and stirred overnight. The solid was collected by filtration, washed with ethanol, and air dried to afford 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (17.9 g, 49% yield). 1H NMR (400 MHz, DMSO-d6)™ 14.34 (br. s., 1H), 7.93-7.98 (m, 2H), 7.88 (d, J=7.78 Hz, 1H), 7.77 (t, J=7.65 Hz, 1H), 7.71 (d, J=8.53 Hz, 1H), 7.54 (d, J=12.05 Hz, 1H), 4.03 (s, 3H), 2.38 (s, 3H); MS (m/z) 380.1 (M+H+).
Reaction SMILES: CC(C)=O.[C:5]([O:9][C:10]([N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([O:33]C)=[O:32])=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>O>[C:5]([O:9][C:10]([N:12]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([OH:33])=[O:32])=[CH:23][C:22]2=[O:35])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)O)c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To 11 mL of acetone solution containing 1.1 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2.2 mL of water solution containing 0.23 g of sodium hydroxide was added at room temperature, and stirred at 50° C. for 30 min. After cooled to the room temperature, the solvent was removed under reduced pressure, 40 mL of water was added, and adjusted to pH 4 with 2 mol/L hydrochloric acid. The resulting solid was filtered to afford 0.97 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: Clc1ccc(CCBr)cc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3ccc(Cl)cc3)cc12

Procedure:
6-[2-(4-Chloro-phenyl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 28% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-Bromo-ethyl)-4-chloro-benzene.
Reaction SMILES: [F-].[Cs+].[CH3:3][O:4][C:5](=[S:27])[NH:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[C:15]([F:26])[CH:14]=2)[CH:12]=1>C(O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5](=[S:27])[NH:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=[C:8]([C:12]#[N:11])[C:7]#[N:6])[CH2:21][CH2:20]3)=[C:15]([F:26])[CH:14]=2)[CH:12]=1
Reactant: COC(=S)NCc1cn(-c2ccc(N3CCC(=O)CC3)c(F)c2)nn1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=S)NCc1cn(-c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of malononitrilc (22 mg, 0.33 mmol) and CsF (42 mg, 0.28 mmol) in ethanol (5 ml) was added {1-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}-thiocarbamic acid O-methyl ester (100 mg, 0.28 mmol), obtained in Example 82. The reaction mixture was allowed to stir at room temperature for 2 h and then diluted with ethyl acetate (100 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:1), the title compound was obtained as white solid (45 mg, 40%). Mp. 198° C.
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(=N)N
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)cc1

Procedure:
Reaction of acetamidine with 4-chlorostyrylsulfonyl chloride according to the above procedure affords N-[(4-CHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 161°-163° C., crystallized from ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:36][CH:37]=O)[CH2:25][N:26]([CH3:35])[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=[CH:21][C:22]=1[Cl:23].ClCCl.CO>O>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:36][CH2:37][N:13]2[CH2:14][CH2:15][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[S:2]([CH3:1])=[O:3])[CH2:11][CH2:12]2)[CH2:25][N:26]([CH3:35])[C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CS(=O)c1ccccc1C1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(2-methylsulfinylphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-benzamide, the title compound was prepared. Chromatography with dichloromethane:methanol followed by conversion to the hydrochloride salt gave a white solid; mp 71°-144° C.; MS: 557; NMR (CD3OD): 1.9-2.3 (m, 6), 2.4 (s, 1), 2.7-2.8 (two s, 3), 2.9-3.4 (br, 6), 3.5-3.9 (m, 4), 7.0 (m, 4), 7.3-7.6 (m, 7), 7.5-7.6 (m, 2). Analysis for C30H34Cl2NO2S·1.0 HCl·1.0 H2O: Calculated: C, 60.45; H, 6.26; N, 4.70; Found: C, 60.43; H, 5.91; N, 4.63.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:18])=O>>[C:1]12([CH2:11][CH2:12][C:13]([Cl:18])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCC12CC3CC(CC(C3)C1)C2

Procedure:
3-(1-Adamantyl)propanic acid was reacted with thionyl chloride as describe in Example 10A to provide the title compound as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CCOc1cnc(-c2ccc(C=CCCCO)cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cnc(-c2ccc(CCCCCO)cc2)nc1
Yield: 70.3 %

Procedure:
A mixture of 12 g of 2-[4-(5-hydroxy-1-pentenyl)phenyl]-5-(ethoxy)pyrimidine, 2 g of palladium on active charcoal (10 w/w %) and 150 ml of ethyl acetate was hydrogenated at normal pressure and room temperature until one molar equivalent of hydrogen had been taken up. The inorganic material was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel with hexane/ethyl acetate (vol. 8:2). Recrystallization from ethyl alcohol gave 8.5 g of pure 2-[4-(5-hydroxy-1-pentyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[CH2:12](I)[CH3:13]>>[CH2:12]([C:10]1[O:9][C:8]2=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=1)[CH3:13]
Reactant: CCI
Reactant: COc1nccc2ccoc12
Product: CCc1cc2ccnc(OC)c2o1

Procedure:
Starting from 7-methoxyfuro[2,3-c]pyridine (4.5 g) and ethyl iodide (4.0 ml). Purification by column chromatography on silica eluting with 70% hexane in ethyl acetate gave the title compound (30 g) as a colourless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:25](=[O:26])[CH2:24][Cl:23])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a suspension of HCl salt of 2-amino-6(5H)-phenanthridinone (3.4 g, 0.014 mol) in ethyl acetate (200 mL) was added saturated solution of sodium bicarbonate (200 mL), followed by addition of chloroacetyl chloride (5.6 mL, 0.07 mol). The reaction mixture was stirred at room temperature for 2 days. The solid that separated out was filtered and washed thoroughly with cold water. It was then dried under vacuum to give N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-chloroacetamide (3.35 gm, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)Oc1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
In a solution of 25.0 g of 3,5-dichlorophenyl boric acid in 200 mL of tetrahydrofuran and 100 mL of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 500 mL of ice water was added, and extracted with ethyl acetate (500 mL×1). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 25.7 g of the aimed product as colorless oily substance.