Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[C:6]2=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC([O-])(C)C.[Na+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=3[CH3:14])[C:6](=[O:18])[C:7]3([CH2:15][CH2:16][CH2:17]3)[CH2:8]2)=[CH:22][CH:21]=1
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2=O
Reactant: Clc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1cc2c(c(C)c1C)N(c1ccc(Cl)cc1)CC1(CCC1)C2=O
Temperature: 105 °C
Yield: 65.5 %

Procedure:
6′-Methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (300 mg) was mixed with 1-chloro-4-iodobenzene (465 mg), NaOtBu (187.4 mg) and [PdBr(tBu3P)2]2 (20 mg). The reaction tube was then sealed with rubber septum, the air was evacuated, then it was flushed with nitrogen. This process was repeated three times, and then toluene (1.5 mL) was added. The reaction tube was then heated in a 105° C. bath for 2 hours. The mixture was then cooled, quenched with water, and extracted with EtOAc. The organic phase was washed with brine, dried and evaporated to give a crude mixture, that was eluted on a silica column (Hexane: EtOAc; 10:1.5-10:2) to give 1′-(4-chlorophenyl)-6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (285 mg) as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=7.399 (s, 1H), 7.16-7.09 (m, 2H), 6.81-6.73 (m, 2H), 4.07 (s, 2H), 3.86 (s, 3H), 2.36-2.23 (m, 2H), 2.13 (s, 3H), 1.99-1.78 (m, 1H), 1.76 (s, 3H), 1.69-1.42 (m, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=198.29, 154.39, 149.44, 141.4, 134.46, 132.07, 129.25, 125.87, 124.07, 121.47, 105.15, 60.96, 55.62, 48.86, 28.59, 15.55, 15.52, and 13.09 ppm.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([CH2:16][CH2:17][C:18]#[N:19])([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])#[N:2].C[N+](C)(C)C.[OH-].Cl>>[C:18]([CH2:17][CH2:16][C:5]([CH2:4][CH2:3][C:1]#[N:2])([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])#[N:19]
Reactant: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Product: N#CCCC(CCC#N)(C(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
Diethyl 2,2-bis(2-cyanoethyl)malonate (2 g, 7.51 mmol) was added to TMAH (25% in water, 10.95 g, 30.04 mmol) at room temperature. The mixture was stirred for 24 hours, and was then cooled to 0° C. A mixture of 12M HCl (2.69 cm3, 32.1 mmol) and ice (3 g) was added and the mixture was extracted with CH2Cl2 (5×50 cm3). The extracts were evaporated under vacuum to give 2,2-bis(2-cyanoethyl)malonic acid (0.25 g, 15.8%) as a colorless very viscous oil (lit decomposed. 158° C.).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:33]2[S:37][C:36]3[C:38]([C:42]4[C:47]([O:48][CH2:49][CH2:50][O:51]C5CCCCO5)=[CH:46][N:45]=[C:44]([F:58])[CH:43]=4)=[CH:39][CH:40]=[CH:41][C:35]=3[CH:34]=2)=[N:21][C:22]([NH:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)=[N:23][CH:24]=1>C(O)C>[N:28]1([CH2:27][CH2:26][NH:25][C:22]2[N:21]=[C:20]([C:33]3[S:37][C:36]4[C:38]([C:42]5[CH:43]=[C:44]([F:58])[N:45]=[CH:46][C:47]=5[O:48][CH2:49][CH2:50][OH:51])=[CH:39][CH:40]=[CH:41][C:35]=4[CH:34]=3)[C:19]([F:18])=[CH:24][N:23]=2)[CH:32]=[CH:31][N:30]=[N:29]1
Reactant: Fc1cc(-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)c(OCCOC2CCCCO2)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCCOc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Add pyridinium p-toluenesulfonate (8.23 mg, 0.03 mmol) to a solution of [5-fluoro-4-(7-{2-fluoro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyridin-4-yl}-benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-(2-[1,2,3]triazol-1-yl-ethyl)-amine (190 mg, 0.32 mmol) in ethanol (4 mL). Stir the mixture at 55° C. overnight. Cool the solution. Concentrate the solution in vacuo to a yellow oil. Purify by column chromatography (methylene chloride to 10% methanol in methylene chloride) to afford the title compound (0.14 g, 88%) as a light yellow solid. MS (ES) m/z 496 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[C:11](=[O:16])([O:14][CH3:15])OC.C[O-].[Na+].Cl>O.C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][CH:5]([C:1](=[O:4])[CH:2]([CH3:3])[C:11]([O:14][CH3:15])=[O:16])[CH2:6][CH2:7]1
Reactant: CCC(=O)C1CCOCC1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 33.3 %

Procedure:
In a flask made of glass having an inner volume of 100 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 1.28 g (9 mmol) of 4-propionyltetrahydropyran synthesized in the same manner as in Example 5, 16.0 g (180 mmol) of dimethyl carbonate and 1.2 g (22 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., to the reaction mixture were added 50 ml of ethyl acetate, 3.4 g (24 mmol) of 6 mol/l hydrochloric acid and 15 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=3/1 (volume ratio)) to give 0.60 g (Isolation yield: 33%) of methyl 3-(4-tetrahydropyranyl)-2-methyl-3-oxopropanoate as a colorless liquid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:3])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.8 g., 0.03 mole) (Example 1, Step B) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoate as a viscous oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].C(O)(=O)C>O>[OH:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Acetic anhydride (398 g, 3.90 mol) was added to a stirred suspension of 2-amino-5-nitro-phenol (400 g, 2.60 mol) and acetic acid (1.60 L) at 62.5° C. The reaction mixture was stirred at 62.5° C. for 1 hour, and then cooled to room temperature. Water (2.00 L) was added over 20 minutes to the stirred reaction mixture. After stirring for 1 hour, the solid was collected by vacuum filtration and washed with water and heptane. Drying the product in vacuo at 60° C. yielded 486.7 g (96%, 99.5% by HPLC) of N-(2-hydroxy-4-nitro-phenyl)-acetamide. 1H NMR (DMSO-d6) δ (ppm) 2.18 (s, 3H), 7.70 (m, 2H), 8.30 (d, 1H), 9.45 (s, 1H), 11.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7](=[O:9])[CH3:8].[BrH:10].BrBr.C(OCC)C>C(O)(=O)C>[BrH:10].[Br:10][CH2:8][C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: CC(=O)c1scnc1C
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ncsc1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
220 mg (1.56 mmol) of 1-(4-methylthiazol-5-yl)ethanone are dissolved in 10 mL of glacial acetic acid. 769 μl (4.67 mmol) of hydrobromic acid and 88 μl (1.71 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 350 mg of product obtained have the following characteristics:
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:4][C:5](=[S:17])[C:6]([C:15]#[N:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.Br[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23]>C(O)C>[CH2:20]([O:21][C:22]([C:23]1[S:17][C:5]2[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[C:15]=1[NH2:16])=[O:24])[CH3:19]
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: CC(=O)OCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc2nc(N)nc(-c3ccccc3)c2c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.010 g, 0.438 mmol, 1 eq) was dissolved in 4 ml anhydrous ethanol under nitrogen. 2-Amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile (0.100 g, 0.438 mmol, 1 eq) was added and the reaction was stirred at room temperature for 1 hour. 2-Bromoethylacetate (0.073 g, 0.438 mmol, 1 eq) was added. The reaction was stirred for further 30 minutes at room temperature. Then sodium (0.010 g, 0.438 mmol, 1 eq) dissolved in 1 ml anhydrous ethanol was added. The reaction was then refluxed for 5 hours. The reaction was cooled to room temperature and quenched with water. The precipitate was filtered off and triturated with diethyl ether to yield 2,5-diamino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[C:21]([NH:24][C:25]1[C:26](Cl)=[N:27][CH:28]=[CH:29][CH:30]=1)(=O)[CH3:22].[OH-].[Na+]>C1COCC1>[CH3:22][C:21]1[S:2][C:26]2[C:25]([N:24]=1)=[CH:30][CH:29]=[CH:28][N:27]=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)Nc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus pentasulfide (56.5 g) and Na2CO3 (13.7 g) were mixed together in 400 mL of THF for ~30 min. To this solution, a solution of the product of Step 1 (17.32 g) in 100 mL of THF was added and the mixture was stirred at room temperature overnight. 2M NaOH (500 mL) was added and the mixture was stirred at room temperature for 2 hr. The product was extracted in EtOAc, washed with brine, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc: toluene 20:80; yield: 12.07 g, (83%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N:15]1[CH:16]=[CH:17][C:12]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=3[CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: Ic1ccncc1
Reactant: Nc1cccc2[nH]ncc12
Product: Nc1cccc2c1cnn2-c1ccncc1

Procedure:
Similarly prepared to intermediate 1 from 1H-indazol-4-amine and 4-iodopyridine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1)#[N:15]
Reactant: CCc1cc(Br)ccc1C(=O)OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C#N)ccc1C(=O)OC
Temperature: 100 °C
Yield: 40 %

Procedure:
Charged methyl 4-bromo-2-ethylbenzoate (1.9 g, 7.85 mmol), Zn(CN)2 (1.48 g, 12.56 mmol), Pd (PPh3)4 (1.0 g, 0.94 mmol) and DMF (30 mL) to a flask, the system was then purged with nitrogen and heated at 100° C. for 6 h. The reaction mixture was then filtered. The filtrate was extracted with ethyl acetate and concentrated the organic phase for flash column chromatograph to give 0.6 g of the title compound (40%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz), 3.92 (3H, s), 7.52-7.54 (1H, m), 7.57 (1H, s), 7.90 (1H, d, J=8.0 Hz).
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[C:8]=2[N:9]=1.O>C(O)CO>[CH3:17][O:16][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)OC)sc12
Solvent: OCCO
Solvent: O
Product: C=Cc1ccc(OC)c2nc(N)sc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl ester was dissolved in ethylenglycol/2N KOH (2:1) and stirred at 100° C. for 3 hrs. Then water was added and the mixture was extracted with CH2Cl2, the organic phase was washed with brine and dried over MgSO4. After evaporation the residue was crystallized from CH2Cl2. White crystals (64%); F.p.: 155-159° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCC(=O)C3)nc1
Yield: 52.7 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-2-tetralone (J. Med. Chem. (1978), 21(9), 913-22) (1.98 g, 12.1 mmol), 6-chloronicotinamide (1.90 g, 12.1 mmol) and K2CO3 (2.52 g, 18.2 mmol) gives the title compound (1.80 g), after purification on silica gel (50% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.24 (d, 1H), 8.00 (s, 1H), 7.46 (s, 1H), 7.25 (d, 2H), 7.08 (m, 2H), 7.00 (d, 1H), 3.64 (s, 2H), 2.77 (t, 2H), 2.34 (t, 2H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]([F:18])=[CH:13][CH2:14][CH2:15][CH2:16]Cl>CN(C)C=O>[Cl:11][C:12]([F:18])=[CH:13][CH2:14][CH2:15][CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: FC(Cl)=CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCSCc1ccccc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
2.43 g of benzylmercaptan were mixed with 30 ml of N,N-dimethylformamide and then additioned with 0.7 g of NaH (55% in paraffin oil). Thereupon, at room temperature and under stirring, into this mixture were dripped 3 g of 1,5-dichloro-1-fluoro-pent-1-ene. The mixture was stirred for 5 hours at 25° C. After washing with water, extraction with ether, drying and evaporizing, there were obtained 3 g of raw product purified by chromatography in a column (cis-, trans- isomer mixture) and which had the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1.Br[C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1
Reactant: CC(C)(Br)C(=O)O
Reactant: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)O)ccc21

Procedure:
A mixture of 5.9 g (0.02 mole) of 3-(4-methoxyphenyl)-2-methyl-1-propyl-1H-indole-5-ol, 5.1 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid, and 15 g of potassium carbonate was refluxed in 100 ml of acetone for 48 hours. The acetone was removed in vacuo, and the residue was acidified with 2N hydrochloric acid. After extraction with ethyl acetate, the extracts were dried over sodium sulfate and evaporated. The residue obtained was purified by chromatography on silicagel (eluant: chloroform/methanol (9:1)).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C@H:5]([OH:10])[CH2:6][CH2:7][CH2:8][CH:9]=1.[Cl:11][C:12]([Cl:16])([Cl:15])[C:13]#[N:14]>C(OCC)C>[Cl:11][C:12]([Cl:16])([Cl:15])[C:13](=[NH:14])[O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH:9]=[C:4]1[Cl:3]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCCC=C1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N=C(O[C@@H]1CCCC=C1Cl)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Combine sodium hydride (0.50 g, 60% in oil, 12 mmol) and diethyl ether (50 mL) and cool to 0° C. Add over 15 minutes a solution of (R)-2-chloro-cyclohex-2-enylalcohol (23.0 g, 160 mmol) in diethyl ether (40 mL). Stir until gas evolution ceases. Add a solution of trichloroacetonitrile (20 mL, 200 mmol) in diethyl ether (30 mL). Stir at 0° C. for 30 minutes and then warm to ambient temperature over 1.5 hours. Evaporate the reaction mixture in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[O:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:12]([O:11][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCON
Agent: Cl
Product: CCON=Cc1ccc(F)cc1
Yield: 58 %

Procedure:
Reaction of 4-fluorobenzaldehyde with ethoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5) and distillation (58% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.35 (3H, t, J=7.07 Hz, CH3), 4.24 (2H, q, J=7.07 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.07 (1H, s, CH).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl[CH2:16][CH2:17][CH2:18][OH:19]>C(N(CC)CC)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCCCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 3-chloro-1-propanol according to Method AC (heating to 90° C. for 6 days before addition of further 3-chloro-1-propanol and triethylamine, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (quantitative). LCMS (ES+) 253 (M+H)+, RT 2.53 minutes (Method 1).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)#[N:7].S(Cl)([Cl:17])(=O)=O>C1C=CC=CC=1>[Cl:17][C:13]1[C:8]([C:6]#[N:7])=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: N#Cc1cnccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
In 90 ml of benzene and 9.2 ml of dimethylformamide there was stirred at room temperature cyanopyrazine (12.7 g; 0.12 M) prepared in Step A above, after which there was added over 10 minutes sulfonyl chloride (64.79 g; 0.48 M). The reaction mixture was stirred for 30 minutes in an ice bath, then allowed to warm up to room temperature gradually, after which it was stirred for 5 hours. The benzene layer was decanted, and the reddish oil residue was extracted three times with ether, after which the combined benzene and ether layers were quenched with ice water and cooled in an ice bath. The combined layers were then neutralized with solid sodium bicarbonate, then separated, and the aqueous layer was extracted with ether. The combined organic layers were washed once with a small amount of water, dried with sodium sulfate, filtered, and the solvent evaporated to give the title compound (11 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:24]([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)CCN1Cc2cc(C(O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-amino-6-benzoyl-4H-quinazolin-3-yl)-N-cyclohexyl-N-methyl-propionamide (0.0056 mol) in methanol (60 mL) and THF (30 mL) was stirred at room temperature. Then, NaBH4 (0.0056 mol) was added and the reaction mixture was stirred for 30 min at room temperature. The solvent was evaporated, and the residue was stirred in H2O and then extracted with CH2Cl2. The organic layer was separated and dried, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 94:6 CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])C)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CN[C@H](C(O)=O)C[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28]C=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][C:16]2[NH:28][C:29]3[C:34]([CH:26]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](NC(=O)Cc1cc(F)cc(F)c1)C(C)C
Reactant: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1cc2ccccc2[nH]1)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
A method similar to that used for the preparation of (107a) was used except that methyl-L-triptophane hydrochloride (214 mg) was used instead of methyl-L-valinate hydrochloride to afford the desired product (365 mg). 1H NMR (300 MHz, CDCl3) δ 3.17 (m, 2H), 3.43 (s, 2H), 4.90 (m, 1H), 5.94 (d, 1H, J=7 Hz), 6.62 (m, 2H), 6.71 (m, 1H), 7.12 (m, 1H), 7.17 (m, 1H), 7.36 (d, 1H, J=8 Hz), 7.39 (d, 1H, J=8 Hz), 8.09 (s, 1H). MS APCI, m/z=373(M+1). LC/MS: 2.28 min.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CNC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 2.3 g 5-chlorosulfonyl-2-oxindole in 10 mL 2M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid formed. The precipitate was collected by vacuum filtration, washed with 5 mL of 1N sodium hydroxide and 5 mL of 1N hydrochloric acid and dried under vacuum at 40° C. overnight to give 1.9 g (79% yield) of 5-dimethylaminosulfonyl-2-oxindole.