Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31](CC5C=CC(OC)=CC=5)[CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C)c2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A solution of N-(3-tert-butylphenyl)-7-({2-[(4-methoxybenzyl)(methyl)amino]-pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (454 mg, 0.83 mmol) in DCM (4 mL) and TFA (4 mL) was heated at 50° C. for 18 h. The reaction mixture was allowed to cool to rt and the solvents were evaporated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 94.9%). LCMS: (FA) ES+ 430.2.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[CH3:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2-methylphenylboronic acid (0.051 g, 0.38 mmol) to afford 0.098 g (71%). LC/MS, Retention time=4.75 min; (m/z): calcd for C26H28N4OS (M+H)+: 445.6; found: 445.0.
Reaction SMILES: [C:1]([C:3]1[C:16]2[S:15](=[O:18])(=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CS(C)=O>[NH:20]1[C:1]([C:3]2[C:16]3[S:15](=[O:17])(=[O:18])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:19])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[N:2][N:22]=[N:21]1
Reactant: N#Cc1cccc2c1S(=O)(=O)c1ccccc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2S(=O)(=O)c2c1cccc2-c1nnn[nH]1

Procedure:
4-Cyanothioxanthone-10,10-dioxide (1.35g), sodium azide (0.39g) ammonium chloride (0.32g) and dimethylsulphoxide were heated together at 125°- 130° C. for 6.5 hr. The mixture was cooled, poured into dilute hydrochloric acid and the precipitated product filtered off. It was warmed with 1% sodium bicarbonate solution, filtered, and the filtrate acidified with dilute hydrochloric acid. 4-(5-Tetrazolyl)thioxanthone-10,10-dioxide was filtered off and recrystallised from acetic acid, m.p. 271° C. with decomposition. Found: C 53.50%; H 2.70%; N 18.04%. C14H8N4O3S requires C 53.85%; H 2.58%; N 17.95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]2)[C:34]([F:45])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C:40](=[O:44])[CH2:39]4)[C:34]([F:45])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
A microwave tube was placed 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.13 g, 4.93 mmol) and (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME (22.2 mL) and aqueous Na2CO3 (5.13 mL of 2 M solution, 10.26 mmol) solution. The mixture was deoxygenated with nitrogen for 20 min. To the reaction mixture was added tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol). The reaction was sealed and heated to 120° C. for 30 min. The reaction was diluted with ethyl acetate (40 mL), filtered through Celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification via silica gel chromatography using 10-80% EtOAc/hexanes gradient afforded (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 64a.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccs1
Product: CCC(NC(=O)Cc1cccs1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Pyrrolidinemethanol (2 g, 20 mmol) was dissolved in CH2Cl2 (25 mL) followed by addition of saturated NaHCO3 (25 mL). To this vigorously stirred mixture was added benzylchloroformate via syringe slowly at 0° C. The reaction mixture was then stirred at room temperature for 4 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×80 mL). The combined organic layer was washed with brine, and dried (Na2SO4). Removal of the solvent provided 4.7 g of the title compound, which was used, directly for next step. 1H NMR (CDCl3): δ 7.50-7.30 (aromatic Hs, 5H); 5.17 (s, 2H); 4.04 (brs, 1H); 3.66 (m, 2H); 3.57 (m, 1H); 3.42 (m, 1H); 2.04 (m, 1H); 1.89 (m, 1H); 1.83 (m, 1H); 1.62 (m, 1H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:56]([O:58]C(C)(C)C)=[O:57])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44]C(C)(C)C)=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[C:56]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([OH:51])=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:58])=[O:57]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NS(C)(=O)=O)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)N[C@@H](CCCCN)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a cooled (10° C.) solution of tert-butyl (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-(tert-butoxycarbonyl)propyl]-1-cyclopentylcarbonyl)-O4-tert-butyltyrosinate (13.3 g, 15.0 mmol) in ethyl acetate (27 ml) was added a 5.1M solution of hydrogen chloride in ethyl acetate (70 ml) (357 mmol of HCl). After 30 minutes the initially clear solution deposited a tar. The mixture was stirred at room temperature for 18 hours. The clear solution was decanted off from the tar and the tar triturated with ethyl acetate (75 ml) to give a sticky solid. The decantation and trituration were repeated 5 times to give a hygroscopic solid which was dissolved in water (12 ml). The resulting aqueous solution was washed twice with ethyl acetate, basified with aqueous sodium hydroxide solution to pH 4.0, seeded with the compound of Example 1 and stirred at 45-50° C. for 42 hours. The off-white solids were collected by filtration, washed with water and acetone and dried to give the title compound (1.95 g), m.p. 237-238° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:22]=2[F:21])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1F)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,4-difluorobenzoic acid.
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)C1C=CC=CC=1.C(Cl)(Cl)=O.N.[C:35]([N:45]1C[C@H](OC(Cl)=O)C[C@H]1C(OC)=O)(OCC1C=CC=CC=1)=[O:36]>C1(C)C=CC=CC=1>[C:1]([N:11]1[CH2:19][C@H:18]([O:20][C:35]([NH2:45])=[O:36])[CH2:17][C@H:12]1[C:13]([O:15][CH3:16])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)Cl)CN1C(=O)OCc1ccccc1
Agent: N
Agent: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](OC(N)=O)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of equivalent quantities of N-carbobenzyloxy-trans-4-hydroxy-L-proline, methyl ester from Example 1, part b, and dimethylaniline is treated with a solution of phosgene in toluene. After standing overnight an equivalent quantity of ammonia is passed through the solution of trans-N-carbobenzyloxy-4-[(chlorocarbonyl)oxy]-L-proline, methyl ester. After standing for twelve hours at room temperature, the solution is washed with water, dried over magnesium sulfate, filtered and the solvent evaporated to give trans-N-carbobenzyloxy-4-[(aminocarbonyl)oxy]-L-proline, methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5]([C:7](=[C:10]([S:13][CH3:14])[S:11][CH3:12])[C:8]#[N:9])=O.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])CS>CCO>[C:8]([C:7]1[C:5]([C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)=[C:12]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[S:11][C:10]=1[S:13][CH3:14])#[N:9]
Reactant: CSC(SC)=C(C#N)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CS
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a stirred suspension of 2-(3,4-dichlorobenzoyl)-3,3-bis(methylsulfanyl)acrylonitrile (2.28 g, 7.16 mmol) in EtOH (31 mL) was added ethyl thioglycolate (0.864 mL, 7.88 mmol) and TEA (1.1 mL, 7.88 mmol). The reaction mixture was heated until reflux was achieved and was then allowed to cool. A solid formed. After sitting at rt overnight, the solid was filtered and washed with cold EtOH (100 mL) to give ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-(methylsulfanyl)thiophene-2-carboxylate (2.38 g, 89%). 1H NMR (400 MHz, d6-DMSO) δ: 7.82 (d, 1H), 7.75 (d, 1H), 7.47 (dd, 1H), 4.14 (q, 2H), 2.82 (s, 3H) and 1.11 (t, 3H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34]([C:37]1[CH:38]=[C:39]([CH:43]([CH3:47])[CH2:44][CH:45]=O)[CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35]>>[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]([CH2:44][CH:45]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:47])[CH:38]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)CC=CCc2ccccc2)c1
Yield: 81.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (5.00 g, 11.2 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 7.0 mL, 11.2 mmol, 1.0 equiv.) and 3-(3-isopropylphenyl)butanal (3.20 g, 16.8 mmol, 1.5 equiv.), 2.54 g (82%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:22][O:21][C:19]([C:14]1[C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=[CH:16][N:15]=1)=[O:20]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (30.0 g, 138 mmol) and methyl 3-aminopyrazine-2-carboxylate (21.2 g, 138 mmol) in DMF (200 mL) was heated at about 80° C. for about 16 h. The mixture was allowed to cool to ambient temperature and was neutralized with saturated aqueous NaHCO3. The mixture was diluted with DCM. The layers were separated and the aqueous layer was washed with DCM. The combined organic layers were washed with brine, dried over MgSO4, and eluted through a silica gel plug with EtOAc as the eluent. The combined organic layers were concentrated under reduced pressure to yield 30 g black oil. The material was diluted with DCM and the insoluble materials were removed by filtration to yield 2.0 g of the title compound. A second crop was obtained similarly to yield 1.8 g. The remaining filtrate was purified by flash silica gel chromatography using EtOAc as an eluent to yield an additional 3.1 g of the title compound (6.9 g, 15%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 272.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 15 gm (78.5 mMol) 2-bromo-4-fluorophenol, 11.2 mL (86.4 mMol) ethyl 2-bromopropionate, and 13 gm (94.2 mMol) potassium carbonate was heated at reflux for 3 hours. At this point 0.1 gm potassium iodide were added and reflux continued for another 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 19.8 gm (87%) of the desired compound as a clear oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:13][CH:14]([NH:21][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC(C)N
Reactant: O=C(Cl)CCCc1ccccc1
Product: CCCCCCC(C)NC(=O)CCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with dibroane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19]C)=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[OH-].[Na+].[BrH:25]>>[Br:25][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: CCc1nc2cc(OC)ccc2n1-c1ccc(CCCl)cc1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCBr)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid (60 mL) was stirred at 100° C. for 6 h. After cooling, the mixture was neutralized with 2N aqueous NaOH and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 890 mg (quant.) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.64 (4H, s), 7.16 (2H, m), 6.97–7.01 (1H, m), 3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q, J=7.8 Hz), 1.29 (3H, t, J=7.8 Hz).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[C:40]#[N:41])=[CH:35][CH:34]=2)O1.COCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:47]=[CH:46][C:36]([O:37][C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[C:40]#[N:41])=[CH:35][CH:34]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3C#N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 67.8 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.29 g, 5.19 mmol, 1 equiv), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.0 g, 6.2 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.329 g, 0.311 mmol, 0.06 equiv), DME (21 mL), and sodium carbonate monohydrate (1.54 g, 12.5 mmol, 2.4 equiv) in water (16 mL) was heated at 85° C. for 60 h. Additional tetrakis(triphenylphosphine)palladium (0.100 g, 0.02 equiv) was added and the reaction mixture was heated at 85° C. for 6.5 h. The reaction mixture was allowed to cool to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and EtOAc (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was triturated from Et2O and purified by column chromatography on silica gel (elution with 1 L of 5% MeOH/CH2Cl2, 1 L of 10% MeOH/CH2Cl2, 1 L of 20% MeOH/CH2Cl2, and 1 L of 25% MeOH/CH2Cl2) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile as a pale yellow solid (1.79 g, 3.52 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.24 (1H, s), 7.94 (1H, d, J=7.7 Hz), 7.68-7.73 (3H, m), 7.31-7.34 (3H, m), 7.18 (1H, d, J=8.5 Hz), 4.78-4.83 (1H, m), 2.21-2.51 (11H, m), 2.19 (3H, s), 2.05-2.08 (2H, m), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.16 min. MS: MH+ 509.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[ClH:1].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][N:21]([CH3:22])[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNC/C=C/C#CC(C)(C)C
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 1.77 g (10 mmol) of 1-chloromethylnaphthalene in 10 ml of dimethyl sulfoxide were added 1.88 g (10 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride and 1.66 g (12 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 16 hours at room temperature, poured into 200 ml of ethyl acetate, washed with 100 ml ×2 of water, a mixture of 80 ml of water and 10 ml of 2N hydrochloric acid, and 50 ml of saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to crystallize. The crystals were suspended in 10 ml of ethyl acetate, cooled, filtered and dried under reduced pressure to obtain 2.95 g (yield: 90%) of the above identified compound as off-white crystalline powder.