Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(F)cc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.37 (tt, J=9.0, 2.3 Hz, 1 H), 7.65 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 7.82-7.91 (m, 2 H), 8.56 (dt, J=7.9, 2.0 Hz, 1 H), 8.75 (dd, J=4.8, 1.6 Hz, 1 H), 9.30 (dd, J=2.0, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1Br.[Sn]([C:66]#[N:67])(CCCC)(CCCC)CCCC>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.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[C:66]#[N:67]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2C#N)CC1
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a Schenk tube were charged compound tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (81 mg, 0.1 mmol), Bu3SnCN (47 mg, 1.5 eq.), Pd(PPh3)4 (23 mg, 0.2 eq.), Bis(tri-t-butylphosphine)palladium (0) (10 mg, O2 eq.). The tube was evacuated and charged with Ar for three cycles. Dioxane (3 ml) was added; the tube was capped and heated at 160 C with stirring for one hour. After cooling, the mixture was diluted with EtOAc and washed with brine once. Organic layer separated, dried over MgSO4 and concentrated. The residue was purified on silica gel. Elution with EtOAc/hexane (0-25%) gave the desired title product (63 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>CS(C)=O.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.3 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.200 g, 0.483 mmol) in DMSO (2 mL) was added ethynyl(trimethyl)silane (0.071 g, 0.724 mmol), copper iodide (0.005 g, 0.007 mmol), bis(triphenylphosphine) palladium(II) chloride (0.200 g, mmol) and TEA (2.0 mL). The reaction mass was stirred at RT for 24 h. The reaction mass was quenched in water and neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.31 (s, 9H), 7.44-7.47 (m, 3H), 7.54-7.71 (m, 3H), 7.94-8.01 (m, 1H), 77.95 (br s, 1H). MS (m/z): 384.29 (M−H)−.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12](I)=[CH:11][C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[C:23]([CH3:36])[C:22]1=[O:37].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:25]4[CH:24]=[C:23]([CH3:36])[C:22](=[O:37])[N:21]([CH3:20])[CH:26]=4)=[CH:11][C:10]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: CCS(=O)(=O)Nc1cc(I)c2oc(C3CC3)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1cc(-c2cc(C)c(=O)n(C)c2)c2oc(C3CC3)cc2c1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
To a solution of the title compound from Step 3 (500 mg, 1.3 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (380 mg, 1.5 mmol) in 10 mL of DMF was added K2CO3 (50 mg, 3.8 mmol), water (2 mL) and Pd(dppf)Cl2 (30 mg) under N2. The reaction mixture was heated to 100° C. for 1 h. The resulting mixture was poured into 100 mL of water and extracted with DCM (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give the title compound (230 mg, 47% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.81 (d, J=3.6 Hz, 1H), 7.67-7.66 (m, 1H), 7.26 (t, J=1.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.54 (br, 1H), 6.36 (d, J=0.8 Hz, 1H), 3.67 (s, 3H), 3.14-3.06 (m, 2H), 2.25 (s, 3H), 2.11-2.00 (m, 1H), 1.38-1.43 (m, 3H), 1.09-0.92 (m, 4H). LCMS: 387 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)cc1
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
10 g (0.06 mol) of p-methoxyphenylacetic acid, 30 ml (0.74 mol) of ethanol and 0.11 ml (0.0026 mol) of sulfuric acid were mixed in a 250 ml balloon flask provided with thermometer and reflux cooler. The thus obtained solution was heated to reflux (78° C.) and held for 1 hour 20 minutes. It was then cooled down at room temperature and 50 ml of deionized water were added. The ethanol was evaporated under vacuum and 40 ml of dichloromethane were added over the residual aqueous phase. The thus obtained mixture was stirred and allowed to decant. The organic phase was washed with 30 ml of a sodium bicarbonate saturated solution, was dried and filtered under vacuum. After evaporating the dichloromethane under vacuum, a colorless residue of ethyl p-methoxyphenylacetate weighing 10.41 g was obtained (Yield: 89%)
Reaction SMILES: Cl.CN.[C:4]([BH3-])#[N:5].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=O)[S:12][CH:13]=1.[OH-].[Na+]>CO>[Br:8][C:9]1[CH:10]=[C:11]([CH2:14][NH:5][CH3:4])[S:12][CH:13]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
18 g (260 mmol) of methylamine hydrochloride and then 7.5 g (100 mmol) of sodium cyanoborohydride are successively added to a solution of 10 g (50 mmol) of 4-bromo-2-thiophenecarboxaldehyde in 150 ml of methanol. The reaction medium is stirred at room temperature for 24 hours and then filtered under vacuum. After evaporating the filtrate to dryness, the residue is taken up in dichloromethane. The organic phase obtained is washed with 1N hydrochloric acid solution. The aqueous phase thus obtained is treated with aqueous 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. 4.5 g (44%) of (4-bromothiophen-2-ylmethyl)methylamine are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)OCC[O:27]1.[Mg]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:26](=[O:27])[CH3:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CCCCCCCBr)OCCO1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Mg]
Product: CC(=O)CCCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 18.5 %

Procedure:
By following the procedure as in Reference Example 25 using a Grignard reagent prepared from 3 g of 3,4-dibenzyloxybenzaldehyde, 2.5 g of 2-methyl-(7-bromoheptyl)-1,3-dioxolane, and 0.3 g of magnesium, 0.8 g of 1-(3,4-dibenzyloxyphenyl)-1,9-decanedione was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)[CH2:13][CH2:12]2
Reactant: N#Cc1cccc(CBr)c1
Reactant: COc1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
An ice cold slurry of 5.89 g (42.6 mmole) of K2CO3 and 5.3 g (35.5 mmole) of 5-methoxyindoline in 55 ml of DMF was treated dropwise with a solution of 7.28 g (37.3 mmole) of α-bromo-m-tolunitrile in 50 ml of DMF. After stirring for 1 hour at room temperature, the reaction mixture was concentrated under high vacuum. The residue was partitioned between methylene chloride (250 ml) and water (250 ml). The organic layer was separated, washed with 5% NaOH (300 ml), brine (300 ml), dried over Na2SO4 and concentrated under vacuum to yield 9.28 g (98.9% yield) of α-(5-methoxy-1-indolinyl)-m-tolunitrile.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=1.[C:18](#[N:20])[CH3:19]>>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:19][C:18]#[N:20])=[CH:6][CH:5]=1
Reactant: CC#N
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(C(=CC#N)c2ccccc2)cc1
Yield: 78 %

Procedure:
To a solution of 6.5 g (0.114 mol) of KOH in 70 mL of acetonitrile was added dropwise under argon a solution of 4-methylbenzophenone (22.5 g, 0.114 mol) in acetonitrile (45 mL). After the addition was complete, the reaction mixture was heated at reflux overnight. It was then allowed to cool, poured into ice and extracted with dichloromethane. The organic phase was dried and the solvent was removed to afford 30 g of a crude product that was chromatographed on silica gel (hexane-ethyl acetate mixtures of increasing polarity) to give 19.5 g of the desired product (yield: 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Yield: 18 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-(2-pyridyl)thiophene-2-sulfonyl chloride (13.5 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 18% yield (3.2 mg). MS (ESI+) calcd mass for C16H12N2O4S2 360.023848, found 360.023668.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: O=Cc1ccccn1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccccn1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 5 mL of ethanol solution containing 5-chlorooxindole (167 mg, 1 mmol), 2-pyridine-carboxaldehyde (129 mg, 1.2 mmol) and 3 drops of piperidine was stirred at 80° C. for 6 hours. After cooling the solution to 5° C., yellow precipitate was obtained (200 mg, 78%). MS: m/z 257 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[S:31]([CH3:34])(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:25]([F:24])[CH:26]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)c(F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-(methanesulfonyl)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.71 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]3[CH:21]=[CH:22][C:17]([CH3:28])=[CH:18][CH:19]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: Cc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-p-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.10 min; [M+H]+=372.18.
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])[S:4][CH3:5].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:7]([NH:6][C:3](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[S:4][CH3:5])#[N:8]
Reactant: NCCSCc1ncccc1Br
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCSCc1ncccc1Br)NC#N

Procedure:
Reaction of dimethylcyanodithioimidocarbonate with 2-((2-aminoethyl)thiomethyl)-3-bromopyridine by the procedure described in Example 3 (d) gave N-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-S-methylisothiourea and a mixture of this compound (1.4 g.) and 3-bromo-2-((2-aminoethyl)thiomethyl)pyridine (2.0 g.) was heated at 140° for 6 hours. The product crystallised upon treatment with isopropyl acetate and was recrystallised from aqueous isopropanol to give the title compound (1.1 g.), m.p. 118°-119°. (Found: C, 40.0; H, 3.8; N, 15.9; Br, 29.5; S, 11.9% C18H20N6Br2S2 requires: C, 39.7; H, 3.7; N, 15; Br, 29.4; S, 11.8%)
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N+:22]([O-])=O)[CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1.C=O.O>CN(C=O)C>[CH3:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH:21]([NH2:22])[CH2:1][OH:2])[CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CN1CC=C(c2c[nH]c3ccc(CC[N+](=O)[O-])cc23)CC1
Reactant: C[O-]
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
Sodium methoxide (0.30 g) was added to a solution of the product from step (d) (1.5 g) in DMF (15 ml) at 0° C. To the resulting solution was added dropwise a suspension of paraformaldehyde (0.19 g) in DMF (20 ml). The resulting mixture was stirred at 0° C. for 1.5 hours, then poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated in vacuo to give a yellow oil which was eluted through a silica column using DCM/EtOH/NH4OH (50:8:1) as eluant to give the desired product as an off-white solid (0.85 g) which was recrystallised from ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13](N)[CH:14]=3)[N:9]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=2)=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:52].[K+]>CC#N.O.CCOC(C)=O>[I:52][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[N:8]=[C:7]2[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h
Yield: 52.7 %

Procedure:
To the stirred solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (6.02 g, 13.3 mmol) in MeCN (45 mL) was added p-toluenesulfonic acid monohydrate (3.37 g, 17.7 mmol). After cooled to 10° C., a solution of sodium nitrite (1.84 g, 26.6 mmol), potassium iodide (5.52 g, 33.2 mmol) in water (9 mL) was added dropwise. The resulting dark brown solution was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc and washed with water and 1N Na2S2O3. After dried and concentrated, the crude mixture was column purified with mixture of hexane and EtOAc to give 5-iodo-3-(pyridin-4-yl)-1-trityl-1H-indazole (3.95 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:29]([O:28][CH2:27][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ClCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (4 g, 19 mmol) in THF (70 mL) cooled to 0° C. is added 0.5 M KHMDS (57 mL, 28.5 mmol) in toluene dropwise. The reaction mixture is warmed to room temperature and stirred for 1 h. Chloromethoxymethyl-benzene (4.46 g, 28.5 mmol) is added and the reaction mixture is stirred for another 1 h at room temperature. Water and ethyl acetate are added and the aqueous layer is separated and extracted with ethyl acetate (2×50 mL). The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated to afford the title compound (3 g, 48.3%) as a light yellow liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:29])[CH3:28])[CH:22]=1)=[O:19]>>[CH3:29][N:27]([CH3:28])[C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])[CH:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 2, 6-quinolylcarbonyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 2.91 (s, 6H), 6.58 (m, 1H), 7.2 (m, 2H), 7.43 (d, 1H), 7.65 (m, l1H), 7.82 (d, 1H), 8.01 (s, l1H), 8.17 (m, 2H), 8.32 (d, 1H), 8.59 (d, 1H), 8.7 (d, 1H), 9.02 (s, 1H), 10.05 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+425.
Reaction SMILES: [C:1]1([S:7][CH:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O1CCCC1>[C:1]1([S:7][C:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(Sc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
To a solution of 30 g (86.5 mmoles) of 2-chloro-1-(p-chlorophenylsulfonyl)ethyl phenyl sulfide in 100 ml of tetrahydrofuran was added 12.2 ml (8.88 g, 87.8 mmoles) of triethylamine. After two hours the reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was evaporated down under reduced pressure, first at 15 mm and finally at 0.01 mm (25° C.), to give a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:35])([F:34])[F:33])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[C:16]([C:32]([F:34])([F:33])[F:35])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C)CC3)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 56 (1.14 g, 2.33 mmol) in MeOH (40 mL) was added formaldehyde solution (37% in water, 0.52 mL, 7.0 mmol) and sodium triacetoxyborohydride (1.98 g, 9.33 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours before concentrating under reduced pressure. The mixture was diluted with sat. aq. NaHCO3 (75 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organics were washed with brine and dried (MgSO4) before the solvent was removed in vacuo to give the product as a white solid (1.05 g, 90%). 1H NMR (400 MHz, d6-DMSO) δ 10.22-10.09 (m, 1H), 8.69-8.55 (m, 1H), 8.04-7.95 (m, 1H), 7.58 (s, 1H), 7.43-7.35 (m, 1H), 7.29-7.12 (m, 4H), 6.96-6.84 (m, 1H), 4.13-4.01 (m, 1H), 3.90-3.79 (m, 1H), 3.27-2.88 (m, 4H), 2.83 (d, J=10.0 Hz, 2H), 2.19 (s, 3H), 2.07-1.87 (m, 6H), 1.33 (d, J=6.8 Hz, 3H). LCMS-D: rt 3.03 min; m/z 502 [M+H]+.