Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].CO.Cl[CH:12]([CH3:15])[C:13]#[N:14]>CN(C)C=O>[C:13]([CH:12]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:15])#[N:14]
Reactant: c1nc[nH]n1
Reactant: CC(Cl)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C#N)n1cncn1
Temperature: 0 °C
Yield: 70.2 %

Procedure:
In this example, a mixture containing 13.47 gms (0.195 mole) of 1,2,4-triazole and 10.53 gms (0.195 mole) of sodium methoxide in 200 mls of dimethylforamide was refluxed until no further evolution of the methanol by-product was observed. The reaction mixture was then cooled to 0° C. and then 19.23 gms of 2-chloropropionitrile dissolved in 25 mls of dimethylforamide were added dropwise with stirring. The mixture was then stirred overnight (about 12 to 14 hours) at room temperature and then filtered. The dimethylforamide was then removed by vacuum evaporation. The residue was dissolved in methylene chloride and filtered through neutralized silica gel. The filtrate was evaporated affording 16.73 gms of the title compound as a brown liquid.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ClSCl
Reactant: CCCCCCCCCCCCOC(=O)NC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)N(C)SCl
Temperature: 5 °C
Reaction time: 2.3 h
Yield: 101.3 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 97.4 g (0.4 mole) of n-dodecyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 150 ml of methylene chloride. The addition took 2.3 hr while the temperature was maintained at -10° to 5° C. After stirring for one additional hour at 5° C. the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Triethylamine hydrochloride was removed by extracting the product into 200 ml of hexane. After filtration, the hexane solution was concentrated to give 125.6 g n-dodecyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[C:36]([F:39])([F:38])[F:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>O.C1(C)C=CC=CC=1>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9][CH2:10][CH:11]([N:32]3[CH2:33][CH2:34][C:29]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:25]=4)([OH:35])[CH2:30][CH2:31]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 14.3 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 14 g of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 0.5 g of p-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 145 hours, water formed being removed as an azeotropic mixture with toluene. The toluene is then removed, and the residual oil is dissolved in 100 ml of 90% methanol. To the solution is added slowly 19 g of sodium borohydride under cooling. After the addition is complete, the methanol is removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The objective base thus obtained is converted in a conventional manner into the hydrochloride. Thus is obtained 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as colorless crystals, melting at 274°-277° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[F:10][C:11]([F:34])([F:33])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)=[C:17]([F:32])[CH:16]=1)=[O:13]>O1CCCC1>[Cl:1][C:31]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][C:23]=2[O:22][C:18]2[C:19]([F:21])=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]([F:10])([F:33])[F:34])=[CH:16][C:17]=2[F:32])[NH:29][CH:30]=1
Reactant: O=C(Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)c(Oc2ccnc3[nH]cc(Cl)c23)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
204 mg (1.54 mmol) of N-chlorosuccinimide and 50 μl of 1M aqueous hydrochloric acid are added to a solution of 250 mg (0.70 mmol) of 2,2,2-trifluoro-N-[3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]acetamide in anhydrous tetrahydrofuran (5 ml). The solution is stirred at RT overnight. The title compound precipitates from the reaction mixture. A solid is obtained by filtration with suction and drying.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]2[CH:16]=[C:17]([F:27])[C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=1[O:40][CH3:41]>>[Cl:29][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[C:17]([F:27])[C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)([OH:14])[C:10]([F:13])([F:12])[F:11]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COc1cc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 45, step 3) was reacted with 4-fluoro-3-methoxyphenylboronic acid to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=540.3 [M−H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CO
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1S(C)(=O)=O

Procedure:
To 4-bromo-2-methanesulfonylbenzoic acid (5 g) were added methanol (45 mL) and concentrated sulfuric acid (1.8 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, the solvent was evaporated, and the residue was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g). To a mixture of the obtained methyl 4-bromo-2-methanesulfonylbenzoate (3.34 g), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (295 mg), 2-(dicyclohexylphosphino)biphenyl (399 mg), tripotassium phosphate (3.39 g) and benzophenonimine (2.5 mL) was added 1,2-dimethoxyethane (25 mL), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran (26 mL), 1N hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give methyl 4-amino-2-methanesulfonylbenzoate (1.46 g). Using the obtained methyl 4-amino-2-methanesulfonylbenzoate (1.46 g) and 3-chloropropane-1-sulfonyl chloride (1.03 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (0.53 g) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2ccc(F)cc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (87%) as a colorless solid: mp 194-196° C. (methanol); 1H NMR (300 MHz, CDCl3) δ7.42-7.25 (m, 10H), 7.10-7.04 (m, 2H), 6.67-6.61 (m, 1H), 6.40-6.39 (m, 2H), 6.23-6.19 (m, 1H), 4.81 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 463.8 (M+1).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:6]>>[CH:6]([P:1]([OH:4])(=[O:3])[OH:2])=[CH:5][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OP(O)O
Reactant: CC(=O)c1ccccc1
Product: O=P(O)(O)C=Cc1ccccc1

Procedure:
In this Example, an acid catalyst (ZSM-5-40 zeolite) was used for both the reaction of phosphorous acid (24.6 gm) with 36 gm of acetophenone (at 75° C.) and the subsequent reaction (at 80° C.) to crack the acyl derivative to form SPA. The amount of catalyst used in the first reaction was 12 gm. It was determined that the product contained 77 wt % styrene phosphonic acid (SPA), 17 wt % unreacted phosphorous acid, and 6 wt % Diels-Alder dimer phosphorus compound. The yield of SPA in this reaction was therefore 65% of theory.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; = -1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained 3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyl-dodecane employed). The product has an optical rotation value of [α]D20 = +3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([C:29](O)=[O:30])[NH:27][CH:28]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:29]([C:26]2[NH:27][CH:28]=[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:25]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1ccc(OCCN2CCCC2)c(Cl)c1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: O=C(Nc1ccc(OCCN2CCCC2)c(Cl)c1)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine was converted to the title compound (20 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid following the procedure described in step C of Example 1. MS (ESI) 444 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].CN.[C:16](=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH3:16])=[S:5]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(C(N)=S)c1ccccn1
Agent: CN
Agent: [Na+]
Product: CNC(=S)C(c1ccccn1)N(C)C

Procedure:
A mixture of 7.5 g. of 2-dimethylamino-2-(2-pyridyl)thioacetamide and 15 ml. of 30% aqueous methylamine is heated for 30 minutes, then cooled and 25 ml. of 5% aqueous sodium carbonate solution is added. The solution is extracted with chloroform, the organic solution is dried and concentrated and the residue is recrystallized to give 2-dimethylamino-N-methyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[CH3:13][S:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:16])=[O:15]
Reactant: COCCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOS(C)(=O)=O

Procedure:
The 2-methoxyethanol (Aldrich, 94 mg, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Br:10]C1C=C(O)C=CC=1>>[Br:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][CH:2]=1
Reactant: COc1ccc(Br)cc1
Reactant: Oc1cccc(Br)c1
Agent: *C(F)(F)C(*)(F)F
Product: COc1cccc(Br)c1
Yield: 40 %

Procedure:
2.9 mmol of parabromo-anisole and 15 cm3 of 1.7 M HF--SbF5 superacid are contacted for 55 hours at ambient temperature in a poly(tetrafluoroethylene) container. Chromatographic analysis of the reaction products shows that a mixture of meta-bromo-phenol (25%) and meta-bromoanisole (40%) is formed, in a 65% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1Cl)=[O:11].[SH2:26].[Na]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:26])=[O:11]
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1Cl)OCO3
Reactant: S
Agent: [Na]
Solvent: CCO
Product: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Yield: 77 %

Procedure:
To 10.4 g (0.025 mol) of 8-chloro-[1,3]dioxolo [4,5-g]quinoline-7-carboxylic acid (2-pyridin-2yl-ethyl)-amide in 100 mL of ethanol was added 7.2 g (0.1 mol) of sodium hydrogensulfide and the mixture was heated at reflux for 3 hours. The mixture was cooled and the solids filtered, washed with ethanol, and then with water. The filtrate was concentrated and the solids were suspended in water, collected by filtration, and recrystallized from ethanol to give 6.8 g of the title compound, mp 258°-260° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(N(CC)CC)C>ClCCl>[N:13]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[O:4])[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cn2cccn2)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To a solution of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol) in 5 ml dichloromethane was added pyrazole (304 mg, 4.46 mmol) and triethylamine (0.31 ml, 2.23 mmol). Reaction was stirred at room temperature over night. Reaction was then diluted with 20 ml dichloromethane, washed with 2×25 ml water, 2×25 ml 1N HCl, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane to give 3-[2-(1H-1-pyrazolyl)acetyl]benzonitrile (330 mg, 70%) as a clear oil after drying. ES-MS (M+H+): 212.05
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].[CH2:8]([O:10]C=O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]([NH:5][CH2:4][C:3]([O:2][CH3:1])([CH3:7])[CH3:6])=[O:10]
Reactant: COC(C)(C)CN
Reactant: CCOC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(C)(C)CNC=O
Yield: 92.2 %

Procedure:
To a stirred solution of 2-methoxyisobutylamine (16.4 g, 0.16 mol) and a catalytic amount of p-toluenesulphonic acid (75 mg) at 0° C. was added slowly ethylformate (11.79 g, 12.92 ml, 0.16 mol). After the slightly exothermic reaction ceased, the solution was refluxed for 16 hours, and distilled through a Vigreux column to give 19.36 g (93%) of N-formyl-2-methoxyisobutylamine, bp 74° C./15 mm.
Reaction SMILES: [N:1]1([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate (11.7 g) obtained in Reference Example 81(1) is dissolved in methanol (50 ml), and thereto is added a solution of sodium hydroxide (3.95 g) in water (20 ml). The mixture is then stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure. The residue is diluted with ice-water and washed with diethyl ether. The resulting aqueous layer is acidified with 10% hydrochloric acid and extracted twice chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and collected by filtration to give the title compound (10.1 g).
Reaction SMILES: I[C:2]1[N:23](S(C2C=CC(C)=CC=2)(=O)=O)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([C:10]3[S:14][C:13]([C:15]4([O:19]COC)[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)[C:4]=2[CH:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][N:35]1[CH:39]=[C:38]([C:2]2[NH:23][C:5]3[N:6]=[CH:7][N:8]=[C:9]([C:10]4[S:14][C:13]([C:15]5([OH:19])[CH2:16][CH2:17][CH2:18]5)=[N:12][CH:11]=4)[C:4]=3[CH:3]=2)[CH:37]=[N:36]1
Reactant: COCOC1(c2ncc(-c3ncnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ncnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 160C) (60 mg, 0.10 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 mg, 0.120 mmol) in N,N-dimethylformamide (2.0 mL) was added saturated aqueous bicarbonate solution (1.0 mL) followed by bis(triphenylphosphine)palladium dichloride (7.02 mg, 10.0 μmol). The mixture was heated to 70° C. for 3 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (1 mL), and 4 molar aqueous HCl solution (0.5 mL) was added. The reaction was heated to 60° C. for 2 hours and was then cooled to room temperature. 4 Normal aqueous sodium hydroxide solution (1 mL) was added, and the reaction heated to 80° C. for 1 hour. The reaction was cooled to room temperature, and the pH adjusted to ˜7 with 10% aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid was triturated with diethyl ether to give the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 1.76-2.08 (m, 2H) 2.31-2.45 (m, 2H) 2.54-2.66 (m, 2H) 3.93 (s, 3H) 6.62 (s, 1H) 7.24 (s, 1H) 8.11 (s, 1H) 8.29 (s, 1H) 8.65 (s, 1H) 8.69 (s, 1H) 12.58 (s, 1H); MS ESI(+) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].[S:19](Cl)(Cl)=O.C(N(CC)CC)C>C1COCC1>[CH:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:16])[C:15]3[C:2]4=[N:1][S:19][N:18]=[C:3]4[CH:4]=[CH:5][C:6]=3[C:7](=[O:17])[C:8]=2[CH:9]=1
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)c2c1ccc1nsnc21

Procedure:
The compound 1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL), and thionyl chloride (0.15 g, 20 mmol) is then dripped thereinto; triethylamine (TEA, 3 mL) is lastly added thereinto for catalyzation. After being mixed at room temperature for one hour, the mixture is transferred into a container with 200 mL of icy water for crystallization. After filtration, a precipitate is collected and re-crystallized with hot alcohol, so as to obtain the yellow compound NSC745885 with a melting point of 227-228° C., and the production rate is about 74%.