Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:17][O:16][C:14]([C@@H:9]1[CH2:10][C@H:11]([NH:13][CH:22]2[CH2:23][CH2:24][C:19]([CH3:26])([CH3:18])[CH2:20][CH2:21]2)[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:15]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To methyl (2S,4S)-1-Boc-4-aminopyrrolidine-2-carboxylate (1.07 g, 4.38 mmol) and dimethylcyclohexanone (0.66 g, 5.25 mmol) in DCE (20 mL) was added dropwise NaBH(OAc) (1.39 g, 6.57 mmol) at rt. The reaction mixture was stirred at rt for 4 h, a saturated NaHCO3 aqueous solution was added, and extracted with DCM (50 mL×2) and EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The obtained residue was purified by column chromatography (eluent, EtOAc/Hex=1/2) to give the title compound (1.16 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.O>[C:12]1([CH:11]2[CH2:9][C:8](=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2ccccc21
Yield: 40.5 %

Procedure:
A mixture of 1-(2-hydroxyphenyl)ethanone (30 g, 220 mmol), benzaldehyde (23.3 g, 220 mmol) and borax (84 g, 220 mmol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column to give 2-phenylchroman-4-one (20 g, 40%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:26][C:27]1[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH:12][S:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)(=[O:34])=[O:33])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CS(=O)(=O)c1cc(CN)nc(-c2ccccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(CNS(=O)(=O)c2ccc(Cl)s2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of C-(4-Methanesulfonyl-[2,2′]bipyridinyl-6-yl)-methylamine (40.0 mg, 0.153 mmol), triethylamine (58.0 μL, 0.459 mmol), 5-chlorothiophene-2-sulfonyl chloride (42.0 mg, 0.184 mmol) and DCM (2 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to afford 5-chloro-thiophene-2-sulfonic acid (4-methanesulfonyl-[2,2′]bipyridinyl-6-ylmethyl)-amide as a white solid (20.0 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([OH:14])(=O)=[O:12].O=S(Cl)[Cl:17]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)O
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)Cl

Procedure:
In a similar fashion using route 39 general procedure 96, 2-methyl-6-nitro-benzenesulfonic acid 451 (7.2 g crude), SOCl2 (16 ml) and DMF (0.35 ml) at 90° C. for 3 h gave the title compound (3.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:12][CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]1([S:7][CH:8]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCC(Sc2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCC(Sc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 3-phenylthiocyclopentanone (Syn. Commun., 1987, 17, 1607) (6.00 g, 30 mmol) in dry pyridine (50 ml) was added hydroxylamine hydrochloride (3.20 g, 45 mmol) and the reaction mixture was stirred for 3 h at room temperature. After the solvent was evaporated off, the residue was partitioned between water (50 ml) and ethyl acetate (100 ml), the aqueous layer separated and extracted with ethyl acetate (100 ml). The combined organic layer was washed with 1N aqueous hydrochloric acid (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried (MgSO4) and concentrated under reduced pressure to afford 6.10 g (98%) of the title compound as a pale yellow oil: 1 H NMR δ7.42-7.38 (m, 2H), 7.33-7.22 (m, 3H), 3.71 (m, 1H), 3.00-3.24 (m, 4H), 2.16 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([CH:11]1[C:16]2=[C:17]3[CH2:23][CH2:22][CH2:21][CH2:20][C:18]3=[N:19][C:15]2=[C:14]([CH2:24][C:25]2[O:29][C:28]([CH:30]=[O:31])=[CH:27][CH:26]=2)[CH:13]=[CH:12]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([CH:11]1[C:16]2=[C:17]3[CH2:23][CH2:22][CH2:21][CH2:20][C:18]3=[N:19][C:15]2=[C:14]([CH2:24][C:25]2[O:29][C:28]([C:30]([OH:1])=[O:31])=[CH:27][CH:26]=2)[CH:13]=[CH:12]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC1C=CC(Cc2ccc(C=O)o2)=C2N=C3CCCCC3=C21
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCC1C=CC(Cc2ccc(C(=O)O)o2)=C2N=C3CCCCC3=C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To freshly prepared silver oxide obtained by treating 1.9 g of silver nitrate with 0.9 g of sodium hydroxide in 8 mL of water was added at 0°-5° C. a solution of 1.4 g of aldehyde from Example 159. After 2 hours of stirring at room temperature the reaction mixture was filtered on celite. The filtrate was acidified with 2N-HCl and the product extracted with ethyl acetate. Repeated crystallizations of the crude material (1.3 g) from ethyl acetate-hexane gave 0.8 g (54.7%) of 5-[(1,2,3,4-tetra-hydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)-methyl]-2-furancarboxylic acid as a pale yellow solid, mp 152.5°-155.0° C.
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH2:11][C:12]#[N:13].Cl>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH:11]([C:12]#[N:13])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: CC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(C#N)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (2.4 g) in dimethylformamide (100 ml) was added a solution of 2-bromopropane and 2-methoxy-5-chlorobenzyl cyanide (18.2 g) in dry dimethylformamide (50 ml), keeping the temperature at 20°-30° C. The mixture was then stirred for 30 minutes, water was added cautiously, and the mixture was then poured into ice-water. Hydrochloric acid was then added and the mixture was extracted with dichloromethane, washed with water then with sodium chloride solution, then dried over magnesium sulphate, filtered, and the solvent was then removed to give 25 g of a brown oil. Distillation gave the title product (15 g) as a colourless oil, bp 180° C./20 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C(#N)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][C:3]#[C:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:18]
Reactant: CCNCC
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Solvent: O
Solvent: CC#N
Product: CCN(CC)CC#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 2-(4-chlorobut-2-yn-1-yl)-1H-isoindole-1,3(2H)-dione (200 mg) in acetonitrile (3 mL) was added diethylamine (188 mg) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and added to water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (112 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[C:15]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[N:16]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (172 mg, 1.4 mmol) in 5 ml of THF was added dropwise to a solution of 2,4-dichloro-6-phenyl-[1,3,5]triazine (452 mg, 2 mmol) (ref: WO 0125220, p.190) and diisopropylethylamine (0.35 ml, 2 mmol) in 15 ml of THF at room temperature then stirred for 18 hours. The reaction was filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography (SiO2) eluting with 8:2 dichloromethane: ethyl acetate to afford 233 mg of the desired product. HPLC: Rt 6.803 mins. MS: m/z 313.0 (M+H)
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]([F:39])([F:38])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:35]2[CH2:34][CH2:33][N:32]([CH2:31][C:30]([F:38])([F:39])[F:29])[CH2:37][CH2:36]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: FC(F)(F)CN1CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC(F)(F)F)CC3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-(2,2,2-trifluoroethyl)piperazine were reacted to give 267. LCMS: M+H+=530.2
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:13]([O:17][C:18](=[O:39])[N:19]([CH2:21][C:22]1[CH:27]=[C:26]([CH2:28]Cl)[CH:25]=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:39])[N:19]([CH2:21][C:22]1[CH:27]=[C:26]([CH2:28][N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]2=[O:10])[CH:25]=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH3:20])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(Cc1cc(CCl)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: CC(C)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)C(=O)C1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 4-isopropyl-piperazin-2-one (32 mg, 0.22 mmol) in DMF (2.2 mL) at 0° C. was added NaH (90%, 11 mg). After 30 min, a solution of [5-chloromethyl-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester (96 mg, 0.22 mmol) in DMF (2.2 mL) was added and the reaction was allowed to come to rt and stir overnight. The mixture was quenched with satd. aq. NaHCO3 and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the desired product (94 mg, 79%). MS (ESI): mass calcd. for C27H35Cl2N3O4, 535.20; m/z found, 536.2 [M+H].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].C(Cl)Cl>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOC(=O)c1ccc(CCCN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCCN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1899.1 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) and ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction was cooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water followed by brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get off product 50 g-HP-silica gel column) to yield 1.18 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H) MS (ES); [M+H]+ 421.3
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NCCN2CCOCC2)nc1
Temperature: 85 °C

Procedure:
A resealable tube was charged with a solution of 2-chloro-5-bromopyrimidine (1.00 g, 5.17 mmol), N-(2-aminoethyl)morpholine (0.808 g, 6.20 mmol), diisopropylethylamine (0.801 g, 1.1 mL, 6.20 mmol), and THF (40 mL). The mixture was heated at 85° C. for 20 h. The reaction mixture was concentrated and then purified via column chromatography on silica gel (gradient elution with 0-100% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford 5-bromo-N-(2-morpholinoethyl)pyrimidin-2-amine as a light yellow solid. MS m/z=288 [M+H]+. Calc'd for C10H15BrN4O: 287.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:40](COCC[Si](C)(C)C)[N:39]=[CH:38][CH:37]=2)O1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:36]2[NH:40][N:39]=[CH:38][CH:37]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 19 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 21.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole to afford a yellow wax UPLC-MS (Condition 3) tR=0.97 min, m/z=436.2 [M+H]+, m/z=434.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=6.97 Hz, 3H) 3.26 (br. s, 2H) 3.36-3.44 (m, 2H) 3.44-3.52 (m, 2H) 4.59 (br. s, 1H) 6.53 (d, J=1.96 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.80 (br. s, 1H) 7.84-7.90 (m, 2H) 8.13 (s, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.28 (s, 1H) 12.94 (br. s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[S:22])[NH2:14])(=[O:3])[CH3:2]
Reactant: S
Reactant: CC(=O)N1c2ccccc2CC1C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2CC1C(N)=S
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.00988 mol) and Triethylamine (0.0197 mol) in pyridine (50 ml) was treated with hydrogen sulfide (gas) at room temperature via a bubbler for 2 hours and the resultant saturated reaction mixture was closed and allowed to set for 16 hours. The reaction mixture was poured into 200 ml of an ice water slurry. A voluminous precipitate formed. The mixture was recooled in an ice bath and the precipitate was collected by suction filtration, washed with cold water, and air dried, yielding 1.62 g of 1-acetyl-2,3-dihydro-1H-indole-2carbothioamide (intermediate 13, mp. 194–195° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][N:3]=1.[Li]CCCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>C1COCC1>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a cooled (-78° C.), stirred solution of 2-bromo-5-(tert-butyldimethylsiloxy)methylpyridine (6.8 g, 0.022 mol) in THF (60 mL) was added 1.6M nBuLi in hexanes (14.1 mL, 0.022 mol). After 1 h, tri-n-butyltin chloride (6.1 mL, 0.022 mol) was added and stirring was continued for 3 h. Water was added, and the mixture was warmed to room temperature and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 11.5 g (100%) of product as a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.CS(O)(=O)=O.[N:20](OCCC(C)C)=O>C(O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=3[N:14]=[N:20]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(NCC2CC2)c(N)c1
Reactant: CC(C)CCON=O
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nnn2CC1CC1
Reaction time: 0.25 h

Procedure:
N1-(Cyclopropylmethyl)-4-methoxybenzene-1,2-diamine (10.8 g, 56.2 mmol) was dissolved in ethanol (80 mL) and treated with methanesulfonic acid (3.65 ml, 56.2 mmol) followed by isoamyl nitrite (7.56 ml, 56.2 mmol). The mixture was stirred for 15 minutes, diluted with ethyl acetate (1500 mL) and washed with aqueous saturated bicarbonate solution (500 mL×2). The organic extracts were concentrated in vacuo and the residue was purified by silica gel gradient chromatography (5-50% ethyl acetate in heptanes), providing the titled compound as a tan solid.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)=[O:16]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(CBr)c1cnc(Oc2ccccc2)nc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]5[NH:30][N:29]=[N:28][N:25]=5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Solvent: Cc1ccccc1C
Product: Clc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(-c4nnn[nH]4)cc3)n2)cc1
Temperature: 160 °C
Reaction time: 117 h

Procedure:
The title compound is prepared starting from 4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile. 4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile (0.932 g; 2.5 mMol) is suspended in o-xylene (10 mL) and treated at rt with azidotributyltin (1.66 g; 1.37 mL; 5 mMol). After stirring the yellow suspension at 160° C. for 117 h the reaction mixture is filtered off without cooling and the crystals are washed with o-xylene. Since the reaction is still incomplete, the crude product is resuspended in o-xylene (20 mL) and treated at rt with azidotributyltin (1.37 mL; 5 mMol). After stirring the yellow suspension at 160° C. for 117 h the reaction mixture is filtered off without cooling and the crystals are washed with o-xylene. The crude product is suspended in methanol (1.00 mL), refluxed and filtered without cooling. The crude product is acidified with 4N HCL/methanol and extracted with ethyl acetate. The aqueous layer is basified with 4N NaOH (ca. pH 12) and extracted with ethyl acetate. Upon this treatment, the product precipitates from the aqueous layer and is filtered off to obtain the title compound.