Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1)(=O)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28](=[O:30])[NH:27][N:26]=2)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28](=[O:30])[N:27]([CH2:6][CH:7]3[O:11][C:10]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]4[CH2:8]3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2)o1
Reactant: CS(=O)(=O)OCC1Cn2cc([N+](=O)[O-])nc2O1
Product: O=c1oc(-c2ccc(Br)cc2)nn1CC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 12.3 %

Procedure:
Using 6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl methanesulfonate prepared in Example 40 (3.28 g, 12.46 mmol) and 5-(4-bromophenyl)-3H-[1,3,4]oxadiazol-2-one (1.5 g, 6.22 mmol) gave 5-(4-bromophenyl)-3-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-3H-[1,3,4]oxadiazol-2-one (312 mg, yield 12%) as a light brown powder in the same manner as in Example 534.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C@@H:21]([CH:23]=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][CH:21]([CH:23]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC1(C)CCC(C)(C)C1CBr
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium has dissolved. At 0° C. a solution of N-Boc-D-alaninal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated, as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]=O)=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.C([N:21](CC)CC)C.Cl.NO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:21])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Agent: Cl
Agent: NO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbaldehyde (Preparation 1, 60 g, 194 mmol) in MeCN (1.5 L) was added triethylamine (68.5 mL, 485 mmol) and hydroxylamine hydrochloride (20 g, 291 mmol). The reaction was heated at 60° C. for 3 hours. The reaction was cooled to 0° C., further triethylamine (220 mL, 1.55 mol) was added and TFAA (109 mL, 776 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2 hours. Water (2 L) was added to the reaction mixture and the resulting solid was collected by filtration. The solid was dissolved in DCM (1 L) and the resulting solution was washed with water (2×500 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (58.59 g) in a 99% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([O:7][CH3:21])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C

Procedure:
5.0 g (15.3 mmol) of the compound of Example 15A were dissolved in 150 ml of methanol and 2.2 ml (30.6 mmol) of thionyl chloride were added dropwise at RT. The reaction mixture was then heated under reflux for 4 h. After cooling to RT, the major part of the solvent except for a residual volume of about 50 ml was removed on a rotary evaporator. The residue was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over magnesium sulphate, the mixture was filtered and concentrated. The crude product obtained in this manner was purified by filtration with suction over about 50 g of silica gel with dichloromethane as mobile phase. Re-concentration gave 5.06 g (97% of theory) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13](OC)=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:20][NH2:21])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 65 °C

Procedure:
Methyl 3-(morpholinosulfonyl)benzoate (120 mg, 0.421 mmol) was added to hydrazine (17.52 mg, 0.547 mmol) in methanol and refluxed for 12 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and cooling the reaction mixture, the solvent was removed by vacuum and then compound was purified by column chromatography to yield the title compound as an off white solid (90 mg). 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 8.12 (m, 1H), 8.04 (m, 1H), 7.85 (m, 1H), 7.63 (t, 1H, J=8.0 Hz), 4.19 (m, 2H), 3.71 (m, 4H), 2.97 (m, 4H). ESI-MS: 286.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)C(CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
2,2-Dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydronaphthalene (15.5 g), dissolved in 250 ml of methanol, containing 2.2 ml of triethylamine, is submitted to catalytic hydrogenation, at atmosphere pressure and room temperature, the catalyst being 2.3 g 5% palladium on charcoal, The calculated amount of hydrogen is taken up within 1 hour. The catalyst is removed by filtration and the solvent by evaporation in vacuo. The residue is dissolved in chloroform and the solution is freed from basic material by means of washing with dilute hydrochloric acid and water, respectively. The dried solution is then concentrated in vacuo leaving a mixture containing two stereoisomers of the desired product. This mixture is suitable for further elaboration as described in example 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:14][O:15]C>Cl.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH:14]=[O:15]
Reactant: COC=Cc1c(OC)ccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CC=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
120 mg of 2-methoxy-1-(2-methoxyvinyl)naphthalene was dissolved in 4 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1). The obtained mixture was then stirred at 70° C. for 2 hours. The reaction solution was cooled to a room temperature and then diluted with ethyl acetate. The resultant product was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 115 mg of (2-methoxynaphthalen-1-yl)acetaldehyde. This compound was used in the following reaction without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([CH:33]=[CH:32][CH:31]=1)[NH:27][C:18]1[C:17]2[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9]3)[CH:16]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)COC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CO)C1
Yield: 67.3 %

Procedure:
6-[1-(acetoxyacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (930 mg, 1.85 mmol) (prepared as described in Example 27) and potassium carbonate (385 mg, 2.79 mmol) in methanol (50 ml) was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8). The fractions containing the expected product were combined and evaporated. The residue was triturated with acetone, filtered and dried to give the title product (574 mg, 67%);
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH-:14].[Na+].O>CS(C)=O>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2](=[O:14])[NH:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: Clc1nccnc1N1CCOCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ccnc1N1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A mixture of 4-(3-chloropyrazin-2-yl)morpholine (894 mg, 6 mmol) and aq NaOH (13 mL, 52 mmol) in DMSO (18 mL) was stirred at 80° C. for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-morpholinopyrazin-2(1H)-one as a light yellow solid (807 mg, 92.9%). 1H NMR (300 MHz, CDCl3) δ 11.80 (br s, 1H), 7.05 (d, J=4.2 Hz, 1H), 6.73 (d, J=4.2 Hz, 1H), 3.84 (s, 8H). LCMS (ESI) m/z 182 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][N:41]([CH3:45])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)CCN
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 71.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (15 mg, 0.027 mmol) in DCM (5 mL) was added N,N-dimethyl-1,2-ethanediamine (0.009 mL, 0.083 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (11 mg, 72%).
Reaction SMILES: [OH-].[K+].C[Si]([C:7]#[C:8][C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(C)C.O>CO>[C:8]([C:9]1[CH:23]=[CH:22][C:12]([N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)#[CH:7]
Reactant: CCCCN(CCCC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(N(CCCC)CCCC)cc1
Yield: 112.6 %

Procedure:
Potassium hydroxide (5 mL, 2 M) was added to a solution of 4-trimethysilylethynyl-N,N-dibutylaniline (3 g, 9.1 mmol) in MeOH (100 mL) with stirring. The solution was stirred at 40° C. for 0.5 h, poured into water (200 mL), extracted with Et2O (3×50 mL), washed with water (50 mL), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (2.35 g, 100%) as a brown oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.ClC1C=CC(S[CH2:14][N:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]2=[O:22])=CC=1.C1CCCCC=1>ClCCl>[Cl:4][CH2:14][N:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]1=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=c1ncc(Cl)cn1CCl
Reaction time: 0.25 h

Procedure:
Sulphuryl chloride (3.0 mmol) in dry dichloromethane (10.0 ml) was added to 1-(4-chlorophenylsulphenyl) methyl-5-chloropyrimidin-2-one (see Example 2) (3.0 mmol) in dry dichlormethane 30.0 ml) at -30° C. for 3 mins. The mixture was stirred at -25° C. for 50 mins before cyclohexene (3.5 mmol) in dry dichloromethane (10 ml) was added. After stirring for 15 mins the mixture was filtered, evaporated and the residue washed three times with Pet. ether. Insoluble 1-chloromethyl-5-chloropyrimidin-2-one (0.45g), 84% was used in Example 31 without further purification.
Reaction SMILES: [H-].[K+].[CH:3]1[C:13]2[CH2:12][S:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>COCCOC>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][S:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)CSc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 25 °C
Yield: 12 %

Procedure:
Potassium hydride (35% dispersion in oil, 229 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see U.S. Pat. No. 3,188,322 [Chem. Abs., 63, 8384h (1965)] and I. Udea and S. Umio, Bull. Chem. Soc. Japan, 48(8), 2323 (1975)) (425 mg) in DME (1,2-dimethoxyethane) (20 ml) and the mixture stirred at room temperature for 30 minutes, treated with a solution of (R)-3-chloro-1-(4-methoxyphenethyl)piperidine (see Preparation 1) (507 mg) in DME (5 ml) and heated under reflux for 18 hours. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane as eluant and changing to dichloromethane/saturated methanolic ammonia (98:2). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (100 mg, 12%), [α]58925 -60.9° (c=0.57 in ethanol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)c1
Yield: 74 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(4- trifluoromethylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Colorless prisms. Melting point: 142 to 143° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:4][CH2:3]1>CO.CCO.[Pd]>[O:31]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3=CCS(=O)(=O)CC3)s2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCS(=O)(=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
N-{3-[2-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 135, 100 mg, 0.214 mmol) was dissolved in a 1:2 v/v mixture MeOH/EtOH (15 mL). Palladium on carbon (57.0 mg, 0.054 mmol) was added, and the reaction was flushed with hydrogen (3×). The reaction was stirred under hydrogen atmosphere at room temperature for 72 hrs. The reaction was filtered through a pad of Celite and concentrated under reduced pressure. Column chromatography on silica (gradient elution, 0 to 75% EtOAc in hexanes) afforded the title compound (0.073 g, 0.156 mmol, 72% yield) as a colorless foam. MS ESI: [M+H]+ m/z 469.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.83 (d, J=4.9, 1H), 7.99 (m, 2H), 7.45 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.16 (bs, 1H), 3.43 (m, 1H), 3.34 (m, 2H), 3.18 (m, 2H), 2.39 (m, 2H), 2.26 (s, 3H), 2.31 (m, 2H). rhSYK activity=+++.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Br)ccc1F
Temperature: 25 °C
Yield: 66 %

Procedure:
Dissolve 4-bromo-1-fluoro-2-nitrobenzene (5.00 g, 22.73 mmol) and SnCl2 (dihydrate, 25.46 g, 113.6 mmol) in ethanol (100 mL) and heat to reflux overnight. Cool to room temperature and concentrate in-vacuo. Dissolve residue in ethyl acetate and basify with saturated aqueous NaHCO3. Filter through a pad of Celite and extract filtrate with ethyl acetate. Dry (MgSO4) and concentrate organics to a brown oil. Chromatograph on 90 g silica gel, eluting with 5% to 10% ethyl acetate/hexanes affords 2.85 g (66%) of the title compound as a tan oil. MS (ES) 191 (M+H); HPLC shows 99% purity.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:33])[CH:25]=2)=[O:23])[CH2:11]1)=[O:7])(C)(C)C.[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38](C(O)=O)=[C:37]([O:45][CH3:46])[CH:36]=1>>[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])[CH2:11]2)=[O:7])=[C:37]([O:45][CH3:46])[CH:36]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(6-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-hexyl)-1-methyl-1 H-indole-3-carboxamide (0.62 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.28 g) to give N-(6-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)hexyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 3 g (23.2 mmol) of trans-4-methylamino-cyclohexanol in 120 mL of CH2Cl2 were added 4.2 mL (24.4 mmol, 1.05 eq) of N,N-diisopropylethylamine followed by 5.96 g (24.4 mmol, 1.05 eq) of 4-(trifluoromethyl)-benzenesulfonyl chloride in 50 mL of CH2Cl2. The mixture was stirred at RT over night and the organic phase was extracted with 1M KHSO4, followed by 5% NaHCO3. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-hexane:EtOAc 1:1 as eluent yielded 6.0 g (77%) of trans-N-(4-hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as off-white solid, MS: 338 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:32][CH2:33][CH3:34])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodopropane and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-propyl-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 534.8 ([M+NH4]+)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([N:9]([CH:17]2[CH2:19][CH2:18]2)C(=O)OC(C)(C)C)[N:5]2[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]2[N:3]=1.[N:25]1([C:31]2[N:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)(C)C>[CH:17]1([NH:9][C:6]2[N:5]3[N:20]=[CH:21][C:22]([CH:23]=[O:24])=[C:4]3[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:31]4[N:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])[CH2:26][CH2:27]3)[C:7]=2[CH3:8])[CH2:18][CH2:19]1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1N(C(=O)OC(C)(C)C)C1CC1
Solvent: CC(C)O
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Tert-butyl 5-chloro-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (60 mg, 0.17 mmol) was mixed with 2-(piperazin-1-yl)nicotinonitrile (64 mg, 0.34 mmol) in i-propanol (1 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was dissolved in (1:1) TFA/DCM (4 mL) and stirred at room temperature for 1 hour. The reaction was evaporated to dryness, quenched with 3N NaOH, filtered, washed with water, and dried under vacuum The product, 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile, was further purified by preparative TLC using 5% acetone/dichloromethane as the eluent (40 mg, 58% yield). LCMS (M+1=403)