Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[N+:16]([O-])([OH:18])=[O:17]>>[F:6][C:7]1[CH:8]=[C:9]([C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 520 cm3 of sulphuric acid, stirred and cooled to 0° C., 60 cm3 of fuming nitric acid are added in the course of 30 minutes. 100 g of 3,4-difluorobenzaldehyde are added in the course of 30 minutes at approximately 0° C. to the solution obtained. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred for a further 3 hours at this temperature. After cooling to approximately 5° C., the reaction mixture is introduced in the course of 30 minutes with vigorous stirring into 1,200 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 600 cm3 of toluene. The combined organic extracts are washed with 3 times 1,000 cm3 of water and concentrated under reduced pressure (20 kPa) to 50° C. 113 g of 3,4 -difluoro-6-nitrobenzaldehyde are obtained in the form of a brown oil, which is used in the subsequent synthesis without further treatment.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of valeryl chloride (13.3 mL, 112 mmol) in dichloromethane (35 mL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (100 mL), and the reaction was stirred overnight at room temperature and then stirred for one hour with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to provide 11.1 g of N-(4-chloroquinolin-3-yl)pentanamide as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[NH:9][C:6]2=[CH:7][N:8]=1)#[N:2].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[O:19]=[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:12]([C:10]1[NH:9][C:6]2=[CH:7][N:8]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[CH:11]=1)=[O:14]
Reactant: N#Cc1cc2cc(C(=O)O)[nH]c2cn1
Reactant: NCC(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1cc2cc(C(=O)NCC(=O)c3ccccc3)[nH]c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 62, 0.035 g, 0.19 mmol) in THF (15 mL) under argon was added 2-aminoacetophenone hydrochloride (0.036 g, 0.21 mmol), N-methylmorpholine (25 μM, 0.23 mmol) and DMTMM (0.072 g, 0.27 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (100 mL). The combined organic extract was washed with 1N NaOH (40 mL), saturated sodium chloride (40 mL), dried (MgSO4), filtered and concentrated in vacuo. Crude material was purified by chromatography in hexane/ethyl acetate (1:2) and recrystallised from methanol to give the title compound. m/z (ES+)=304 [M+H]+; RT=4.37.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O-:20].[Na+].[OH-].[Li+]>CO.O>[CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][N:18]=1)[C:14]([NH2:15])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[O-]
Reactant: CCCCCCCCCOc1cc(C#N)ccn1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCOc1cc(C(N)=O)ccn1
Temperature: 25 °C
Yield: 227 %

Procedure:
A solution of 2-(nonyloxy)isonicotinonitrile (250 mg, 1.0 mmol, 1 equiv.) and sodium methoxide (10 mg, 0.1 mmol, 0.1 equiv.) in dry CH3OH (10 ml) was stirred at r.t. for 2.5 h. A solution of lithium hydroxide (24 mg, 1.0 mmol, 1 equiv.) in water (1 ml) was added and the reaction mixture was heated under reflux for 3.5 h. After cooling at r.t., the mixture was poured into water (40 ml). The precipitant solid was filtered and dried in vacuo at 50° C., to give the desired compound as a white solid (60 mg, 23%), mp 108-110° C. HPLC-MS (method 1): m/z 265 [M+H]+, Rt=5.08 min.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14](S(C)(=O)=O)[N:15]=1>C1COCC1.O>[Cl:9][C:10]1[C:11]2[CH2:22][CH2:21][CH2:20][C:12]=2[N:13]=[C:14]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(OC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of cyclopentanol (0.287 g, 3.33 mmol) in THF (5 mL) was added sodium hydride (0.016 g, 0.67 mmol) and the mixture stirred at rt under a nitrogen atmosphere for 30 min. Then, the mixture was added treated with a solution of 4-chloro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.155 g, 0.67 mmol) dropwise in THF (2 mL) and the resulting mixture stirred at rt for 2 h. After this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0:080 g, 52%). MW=238.71. 1H NMR (CD3OD, 300 MHz) δ 5.64-5.40 (m, 1H), 2.90 (t, J=7.6 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.21-2.08 (m, 2H), 1.90-1.71 (m, 4H), 1.71-1.59 (m, 2H), 1.38-1.18 (m, 2H); APCI MS m/z 239 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[N:6][N:7]=1.[Na].[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>C(#N)C>[NH:12]1[C:11]([NH:10][C:2]2[N:3]=[N:4][C:5]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[N:6][N:7]=2)=[N:15][N:14]=[N:13]1
Reactant: Clc1nnc(Cl)nn1
Reactant: Nc1nnn[nH]1
Agent: [Na]
Solvent: CC#N
Product: n1n[nH]c(Nc2nnc(Nc3nnn[nH]3)nn2)n1
Temperature: 25 °C

Procedure:
To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1.51 g, 10 mmol) in acetonitrile (70 ml) was added the sodium salt of 5-amino-1H-tetrazole (2.14 g, 10 mmol). The mixture was refluxed for 24 hours then allowed to cool to room temperature. The suspension was centrifuged until the supernatant liquid was clear. The liquid was decanted and the brown solid washed successively with acetonitrile and water. With each wash the solid was separated from the solvent by centrifugation followed by decantation. The isolated crude yield was 1.5 g (60%), this material was recrystallized from DMSO/methanol yielding an orange brown powder mp 264° C. dec; 1H NMR (deuteriomethylsulfoxide) ∂ 12.5 (br s, 4H); 13C NMR (deuteriomethylsulfoxide) ∂ 151.74, 158.25; IR (KBr) 3421, 3000, 1615, 1436, 1127 cm−1. A gas pycnometer density of 1.76 g/cm3 was also determined and a drop height of 195 cm was measured (Type 12, HMX=24-27 cm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=3.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[C:15]1([C:10]2[CH:9]=[CH:8][C:7]3[N:6]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:5]4[C:13]([C:12]=3[CH:11]=2)=[CH:14][C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-n2c3ccc(Br)cc3c3cc(-c4ccccc4)ccc32)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3c(c2)c2cc(-c4ccccc4)ccc2n3-c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
The 3-bromo-6-phenyl-N-(4-methylphenyl)carbazole (3.20 g) and 4-methoxyphenylboronic acid (1.65 g) were added to a solvent mixture of toluene (30 mL) and ethanol (8 mL), followed by bubbling with nitrogen. Then, tetrakistriphenylphosphine palladium (150 mg) and 21.2% aqueous sodium carbonate solution (7.80 g) were added to the mixture, and the resultant mixture was refluxed under nitrogen flow for 3 hours. The mixture was diluted with toluene. The toluene layer was washed with water and dried and the toluene was evaporated. The residue was treated through silica gel column chromatography (eluent: toluene), to thereby obtain 2.30 g of 3-phenyl-6-(4-methoxyphenyl)-N-(4-methylphenyl)carbazole as colorless powder.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:3])[CH2:29][CH2:28]1
Reactant: CC(Br)c1ccc2ncccc2c1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc2ncccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 6-(1-bromoethyl)-quinoline (0.44 g, 1.86 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.35 g, 1.24 mmol) in DMF (10 mL) was added K2CO3 (0.26 g, 1.86 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and was then treated with H2O (100 mL) to provide 0.52 g (96%) of a white precipitate after filtration. MS (ESI(+)Q1MS) m/z 435 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 8.82-8.88 (m, 1H), 8.30-8.37 (m, 2H), 7.97-8.02 (m, 1H), 7.76-7.89 (m, 2H), 7.58-7.64 (m, 1H), 7.47-7.55 (m, 1H), 7.22-7.34 (m, 2H), 5.23 (s, 1H), 3.76 (dt, 1H), 3.37-3.52 (m, 1H), 2.96-3.04 (m, 1H), 2.80-2.89 (m, 1H), 2.09-2.21 (m, 2H), 1.82-1.98 (m, 2H), 1.50-1.71 (m, 2H), 1.40 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexane. Enantiomers had retention times of 4.1 and 6.3 minutes. The optical rotations of the enantiomers were [α]D (90:10 CH2Cl2:MeOH, 25° C.)=+19.2 and −14.7, respectively.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24](C1C=CC=CC=1)(C1C=CC=CC=1)[O:25][SiH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.F[C:45](F)(F)[C:46](O)=O>ClCCl>[NH2:7][C@H:8]([CH2:24][O:25][Si:26]([C:27]([CH3:28])([CH3:30])[CH3:29])([C:46]1[CH:45]=[CH:10][CH:9]=[CH:8][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[O:23])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN1CC(C(=O)c2ccc(F)cc2)C1)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H](N)CCN1CC(C(=O)c2ccc(F)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-carbamic acid tert-butyl ester. (0.188 g, 0.321 mmol) in dichloromethane (5 ml) is treated with trifluoroacetic acid, and stirred at ambient temperature for 0.5 hour. The reaction mixture is diluted with dichloromethane and washed with water and saturated aqueous NaHCO3. The organic phase is dried over MgSO4 and evaporated to afford {1-[(S)-3-Amino-4-(tert-butyl-diphenyl-silanyloxy)-butyl]-azetidin-3-yl)-(4-fluoro-phenyl)-methanone. [MH]+ 505.2.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
To a solution of the title compound from step A (320 mg, 1.1 mmol) in DCM (5 ml) was added TFA (2.1 ml, 27.5 mmol) and the resulting mixture stirred at RT for 4 h. Mixture evaporated and residue dissolved in MeOH and passed through an SCX cartridge (eluting with 2M ammonia in methanol) to form free base. Evaporated and residue lypholized from CH3CN/water to afford the title compound 44 mg (21%) as an orange oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 2.24 (m, 1H), 2.47 (m, 1H), 2.64 (dd, J 12.3 and 9.3 Hz, 1H), 2.73 (m, 1H), 2.87-2.97 (m, 3H), 3.44 (d, J 14.2 Hz, 1H), 4.14 (d, J 14.3 Hz, 1H), 7.17 (dd, J 7.0 and 5.4, 1H), 7.47 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J 4.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:11]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1ccc(Br)c[nH]1
Solvent: O
Product: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Yield: 90.3 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 29.0 mmol, 5.00 g, Example 1 Step 1) and 4-chlorobenzyl bromide (1.2 eq, 34.0 mmol, 7.10 g) according to the procedure described for Example 1 Step 2. After concentration of the solvent, water was added. The aqueous phase was extracted with AcOEt and the combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallized with pentane/Et2O 50/50 to afford 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (26.2 mmol, 7.82 g, 91%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][C:19]1([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:28]([O:27][C:25]([C:19]1([CH2:18][N:13]2[CH2:12][CH2:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([F:16])[CH2:15][CH2:14]2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCC1(F)CCNCC1
Reactant: O=C(OCc1ccccc1)C1(CI)CCOCC1
Product: CC(C)(C)OC(=O)NCC1(F)CCN(CC2(C(=O)OCc3ccccc3)CCOCC2)CC1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 3 from 4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 4 of Example 15) and benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate (step 2 of Example 15).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:26])[NH:27][CH2:28][C:29](=[O:30])[NH:14][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: O=C(CNC(=O)OCc1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and benzyloxycarbonylamino-acetic acid (CA [1138-80-3]).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:28][CH2:29]O>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([S:12][C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[CH3:11])[CH:14]=1)[CH3:29]
Reactant: CCO
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (from the previous step) was dissolved in EtOH (100 mL), conc. H2SO4 (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was submitted to standard workup procedures then purified via silica gel chromatography to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=2[CH:21]=1>>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCc1ccc(Nc2nc(Cl)ncc2Cl)cc1
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccc(CC#N)cc4)n3)cc21

Procedure:
{4-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-acetonitrile was prepared from [4-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one in an analogous manner to Example 1d. White solid 130 mg (96%), MP:163-164, HPLC purity 94%, LCMS: 447.25 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.08-7-11 (m, 3H), 7.01 (s, 1H), 3.84 (s, 2H), 2.67 (bs, 2H), 2.34-2.31 (m, 2H), 2.29-2.18 (m, 2H), 1.58 (s, 2H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[NH:20][N:21]=1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Reactant: Cc1cc(N)n[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(Nc2cc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 200 °C

Procedure:
To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128)(0.53 g, 2.21 mmol) in diphenylether (5 mL) was added 3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixture heated at 200° C. overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mL) was added and the resulting precipitate was isolated by filtration. The crude solid was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-4 as a white solid: mp 242-244° C.; 1H NMR (DMSO) δ 2.27 (3H, s), 6.02 (1H, s), 7.47 (2H, d), 7.53-7.40 (2H, br m), 7.67 (1H, m), 7.92 (1H, m), 8.09 (2H, d), 8.48 (2H, m), 9.20 (1H, s), 12.17 (1H, br s); IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([S:18][CH3:19])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH2:27][CH2:28][CH3:29]>CC(C)=O>[CH2:26]([N:15]1[C:16]([S:18][CH3:19])=[CH:17][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])=[N:14]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC
Yield: 32 %

Procedure:
A solution of 0.8 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-(methylsulfenyl)pyrazole (compound 16), 0.7 g of anhydrous potassium carbonate and 0.4 g of n-butyl bromide in 25 ml of acetone were refluxed for 4 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (eluent: ether/hexane=1/20) to obtain 0.3 g of the desired product in the form of a light brown oil (yield 69.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:31])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Methoxyphenethyl alcohol (50 g) and triphenylphosphine (103 g) were dissolved in methylene chloride (600 ml), followed by the addition of N-bromosuccinimide (70 g) in small portions under ice-cooling, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated, and to the resulting residue was added hexane. The insoluble matters were filtered off, while the resulting filtrate was evaporated, to give the title compound as a colorless oil (50.32 g, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[S:47])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.15 mmol) and P2S5 (70 mg, 0.31 mmol) was heated at 60° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM for 2 times. The DCM solution was combined and concentrated. The residue was purified by flash column to give the title compound as white solid (65 mg).