Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([C:25](O)=[O:26])=[N:10]1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][OH:26])=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.5 g of 1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid in 30 ml of THF, were added dropwise 43 ml of a 1M solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and used without further purification. Yield: 4.3 g.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34](OCCCC)=O>C(#N)C.[Cu](Br)Br>[C:1]1([S:7]([N:10]2[CH:11]=[CH:12][C:13]3[C:14]2=[N:15][CH:16]=[C:17]2[C:18]=3[N:19]([C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21]3)[N:34]=[N:33]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCON=O
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Agent: Br[Cu]Br
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn([C@@H]3CCCN(Cc4ccccc4)C3)c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A stirred solution of 1-benzenesulfonyl-N*4*-((R)-1-benzyl-piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (300 mg, 0.65 mmol) in acetonitrile (6 ml) was treated with copper (II) bromide (174 mg, 0.78 mmol) and n-butyl nitrite (114 μl, 0.97 mmol) and then heated to 70° C. for 2 hours. After cooling, the reaction was quenched by the addition of 1M aqueous HCl solution (ca. 5 ml) and stirred for 5 minutes. The mixture was basified with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to leave a brown residue. Purification by column chromatography on silica gel (gradient: 0 to 60% ethyl acetate in cyclohexane) gave 200 mg (65%) of 6-benzenesulfonyl-1-((R)-1-benzyl-piperidin-3-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene as a brown residue. LCMS (Method B, ESI): RT=3.38 min, m+H=473.5; 1H NMR (400 MHz, CDCl3) δ: 9.18 (s, 1H), 8.21 (m, 2H), 7.82 (d, 1H), 7.57 (m, 1H), 7.53-7.46 (m, 2H), 7.30 (s, 5H), 6.75 (d, 1H), 4.88 (m, 1H), 3.61 (dd, 2H), 3.25 (m, 1H), 3.03 (m, 1H), 2.57 (m, 1H), 2.39-2.17 (m, 3H), 2.10-1.87 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.ONC(=O)[C@@H](O)[C@@H](C([N:64]1[CH2:69][CH2:68][N:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=2)[CH2:66][C@H:65]1[CH3:76])=O)CC(C)C.O>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:66][C@@H:65]2[CH3:76])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@H](O)C(=O)NO
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@@H]1C)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 198 mg; 0.50 mmol; 1.0 eq.) in DMF (4 mL) was added (3S)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 4, 88.6 mg; 0.50 mmol; 1.0 eq.) and the resulting reaction mixture was stirred 48 h at RT. Water was added and the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give an oil. Purification by chromatography (SiO2, gradient from 10% EtOAc in c-hex up to 40% EtOAc in c-hex in 15 min) gave the title compound as a colorless oil (43 mg; 22%) (mixture of 2 diastereoisomers). M+(ESI): 390.3.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH:18][C:19]([C:21]2([NH:26][C:27]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9](=[O:17])[NH:10][CH:11]2CCNC[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1C=O.[OH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[O:48].C1(C[C@@H](NC(C2(NC(C3SC4C=CC=CC=4C=3)=O)CCCC2)=O)C(=O)NC2CCN(CC3C=CC=CN=3)CC2)C=CC=CC=1>>[OH:48][C:47]([C:49]([F:52])([F:51])[F:50])=[O:46].[C:1]1([CH2:7][C@@H:8]([NH:18][C:19]([C:21]2([NH:26][C:27]([C:29]3[S:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[CH:30]=3)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[C:9](=[O:17])[NH:10][CH2:11][CH2:12][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NC2CCNCC2)CCCC1)c1cc2ccccc2s1
Reactant: O=Cc1ccccn1
Agent: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NC2CCN(Cc3ccccn3)CC2)CCCC1)c1cc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1(C(=O)N[C@H](Cc2ccccc2)C(=O)NCCC2CCNCC2)CCCC1)c1cc2ccccc2s1

Procedure:
200 mg (0.31 mmol) of benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-1(R)-(piperidin-4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl}-amide are used for the reaction of reductive amination with pyridine 2-carboxaldehyde (64 mg, 0.6 mmol), to yield, after purification by preparative HPLC according to the method already described in the previous Examples, the desired product benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-1(R)-(1-pyridin-2-ylmethyl-piperidin-4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl}-amide TFA salt (120 mg, 0.16 mmol).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:28][C@@H:27]1[CH:40]=[O:41])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:48]=[C:47]([CH2:49][CH2:50][N+:51]([O-:53])=[O:52])[CH:46]=[C:45]([F:54])[CH:44]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:28][C@@H:27]1[CH:40]([OH:41])[CH:50]([N+:51]([O-:53])=[O:52])[CH2:49][C:47]1[CH:48]=[C:43]([F:42])[CH:44]=[C:45]([F:54])[CH:46]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C=O
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C(O)C(Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add tetrabutylammonium fluoride (0.08 mL, 0.08 mmol, 1.0 M in tetrahydro-furan) to (2R, 5R)-5-Benzyloxy-2-formyl-piperidine-1-carboxylic acid tert-butyl ester (0.27 mg, 0.84 mmol) and 1,3-difluoro-5-(2-nitro-ethyl)-benzene (0.17 g, 0.93 mmol) in 5 mL tetrahydrofuran. Stir at room temperature overnight and concentrate. Subject the residue to silica gel chromatography, eluting with from 100% hexane to 90:10 hexane:ethyl acetate to provide the desired compound as a mixture of 3 isomers (0.286 g, 67%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][C:9]([S:14][CH3:15])=[N:8][C:7]=2[NH:6][CH:5]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Cl:13][C:11]1[C:12]2[C:4]([CH2:3][CH2:2][O:1][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:5][NH:6][C:7]=2[N:8]=[C:9]([S:14][CH3:15])[N:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CSc1nc(Cl)c2c(CCO)c[nH]c2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The hydroxyethyl pyrrolopyrimidine (1.4) (1.91 g, 7.8 mmol) was dissolved in DMF (25 ml) and tert-butyldimethylsilyl chloride (1.77 g, 11.7 mmol) and imidazole (1.6 g, 23.5 mmol) added and the solution stirred at room temperature for 6 hours. The solvent was removed and the product dissolved in chloroform, washed with water and the solvent evaporated. The product was precipitated by trituration with methanol, filtered and dried to give an off-white solid. A second fraction was obtained by concentration of the mother liquors. Yield 2.51 g, 89%. δH −0.07 (6H, s, 2×CH3), 0.80 (9H, s, C(CH3)3), 2.52 (3H, s, SCH3), 2.94 (2H, t, J 7.0 Hz, OCH2CH2), 3.78 (2H, t, J 7.0 Hz, OCH2), 7.29 (1H, s, H6), 12.10 (1H, s, NH) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]([F:23])([F:22])[F:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH:25]([CH2:28]Br)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:20]([F:22])([F:21])[F:23])[N:9](/[CH:28]=[CH:25]/[C:26]#[N:27])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: N#CC(Br)CBr
Reactant: Fc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 41.1 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazole (3.045 g), 2,3-dibromopropionitrile (5.33 g), anhydrous potassium carbonate (3.1 g) and triethylamine (5.2 ml) in dry DMF (19 ml) by the process as described for the preparation of Intermediate (3a) to afford a dark brown residue which was purified by FCC using gradient elution with System A (5-15% with 5% incremental increase of ethyl acetate per 500 ml eluant) to afford the title compound (1.449 g) as a white solid. νmax (CHBr3) 2229 cm-1 (C≡N).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH3:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[S:35]([CH3:34])(=[O:37])=[O:36])[CH3:20])=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt (380 mg) in dichloromethane (10 mL) was added triethylamine (0.30 mL) and methane sulfonyl chloride (71 μL). The mixture was stirred at room temperature for 2 h and then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organics were washed with brine (20 mL), dried, reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine as an off-white solid (124 mg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30](=[O:32])N)[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:37])C>C(O)C.O>[C:19]([O:18][C:16]([N:15]1[C@H:11]([CH2:10][CH:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30]([OH:37])=[O:32])[CH2:12][CH2:13][C@H:14]1[C:23]([OH:25])=[O:24])=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O

Procedure:
2.2 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-carbamoylethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 20 ml of ethanol and 5 ml of water. 1.2 g of solid sodium hydroxide were added thereto. The solution was then boiled under reflux for 36 h. For workup, it was cooled to room temperature and neutralized with acetic acid, and the ethanol was removed in vacuo. The residue was diluted with 20 ml of water and adjusted to a pH of 3 with acetic acid. The mixture was extracted 3 times with 30 ml of 5:1 ethyl acetate/butanol each time. The organic phases were combined and concentrated in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:33])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccccc1

Procedure:
By carrying out the operation according to the procedure of Example 24, but starting with 0.21 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-phenylsulfonamide, 17 mg of 80% sodium hydride and introducing iodomethane in two portions at an interval of 3 hours. 80 mg of N-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-N-methylphenylsulfonamide are thus obtained in the form of a white lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.70 (s: 3H); 3.03 (broad t, J=7.5 Hz: 2H); 3.37 (broad t, J=7.5 Hz: 2H); 3.94 (mt: 1H); 4.28 (s: 1H); from 7.20 to 7.35 (mt: 8H); from 7.45 to 7.65 (mt: 3H); 7.74 (broad d, J=8 Hz: 2H)].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>ClCCl>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C1=COCCC1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCCCO1
Yield: 3.7 %

Procedure:
a solution of 25.0 g (290 mmol) methacrylic acid and 27.8 g (330 mmol) dihydropyran in 80 ml of dichloromethane was stirred for 14 hr at room temperature. The reaction mixture was thoroughly extracted with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The residue was distilled to give 1.84 g (10.8 mmol; 3.7% yield) tetrahydropyran-2-yl methacrylate, bp 53° C. at 0.2 torr.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=1.[CH2:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([CH:17]([CH2:21][CH2:22][CH3:23])[C:16]([NH:15][C:11]1[CH:10]=[C:9](/[CH:27]=[CH:26]/[CH2:25][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:14]=[CH:13][CH:12]=1)=[O:24])[CH2:19][CH3:20]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: CCCC(CCC)C(=O)Nc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(CCC)C(=O)Nc1cccc(/C=C/CNC(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
Et3N (1.2 mL) was added to a solution of N-(3-bromophenyl)-2-propylpentanamide (0.6 g, 2.01 mmol), tert-butyl allylcarbamate (1.026 g, 6.55 mmol) and P(o-tol)3 (0.06 g, 0.201 mmol) in DMF (10 mL). The reaction mixture was degassed for 30 min and then added Pd(OAc)2 (0.09 g, 0.409 mmol) was added. The reaction mixture was again degassed for 15 min and then refluxed at 90° C. for 8 h. The reaction mixture was diluted with EtOAc, washed with H2O, brine. The organic layer was concentrated under reduced pressure. Purification by column chromatography(100-200 mesh silica, elution 10% to 15% EtOAc in hexane) gave (E)-tert-butyl 3-(3-(2-propylpentanamido)phenyl)allylcarbamate as a yellow oil. Yield (0.7 g, 37%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.08 (dd, J=1.2, 7.2 Hz, 2H), 6.48 (d, J=16.0 Hz, 1H), 6.26-6.16 (m, 1H), 4.67 (bs, 1H), 3.89 (bs, 2H), 2.17-2.04 (m, 1H), 1.73-1.64 (m, 4H), 1.48 (s, 9H), 1.45-1.14 (m, 4H), 0.91 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C(Cl)=O.ClCCl.[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH2:32])=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH:32][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([C:2]([CH3:3])=[CH2:1])=[CH:12][CH:11]=3)=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1
Reactant: Cn1cc(Br)c2cnc(N)cc21
Reactant: C=C(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
In a 50 ml round bottom flask, 4-(prop-1-en-2-yl)benzoic acid (580 mg, 3.6 mmol) was dissolved in 15 ml toluene, and 2.0 M oxalyl chloride in dichloromethane (3.6 ml, 7.2 mmol) was added slowly. Stirring continued for 3 hours, and then volatiles were evaporated from the reaction mixture. To the residue was added 5 ml toluene and the mixture was concentrated in vacuo to azeotropically remove residual water. The residue was then dissolved in DMA (12 ml) and 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-amine (400 mg, 1.8 mmol) was added. Stirring continued at 50° C. for another 3 hours. The mixture was then poured into ice water. The precipitate was collected and dried to obtain the product N-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (6A, 440 mg, 67%). This was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][OH:10])[CH2:4]1.[CH2:11](Br)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][OH:10])[CH2:4]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCBr
Reactant: OCC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCCC(CO)C1
Yield: 79 %

Procedure:
A] A 1N solution of sodium hydroxide (174 ml, 0.17 mole) was added to a mixture of 3-piperidinemethanol (20 g, 0.17 mole) and butyl bromide (23 ml, 0.2 mole) in ethanol (200 ml). The reaction mixture was refluxed for 4 hours, then the solvent was evaporated under vacuum. The aqueous solution was acidified with HCl and washed with ethyl ether, then treated with a 32% solution of sodium hydroxide to pH-12 and extracted with ethyl ether. The combined organic phases were anhydrified over sodium sulfate and the solvent was evaporated under vacuum. The crude was purified by distillation yielding 23 g of N-butyl-3-piperidinemethanol (b.p.: 115-117/6 mmHg) (yield: 79%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]2)[C:7]1=[O:26])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]1([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]1)[C:7](=[O:26])[N:6]2[CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Yield: 100 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′ H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 100% yield. The product was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][P:34]([CH3:38])(=[O:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][P:34]([CH3:38])(=[O:37])[CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)[N:14]=1)=[O:4]
Reactant: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
tert-Butyl 4-(4-((4-((3-(methoxycarbonyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I32) (0.180 g, 0.309 mmol) was dissolved in dry DMF (10 mL) under an atmosphere of nitrogen. 10% Pd/C (0.100 g) in EtOAc (10 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the reaction was flushed with nitrogen gas and Pearlman's catalyst (0.150 g) in EtOAc (5 mL) was added. The atmosphere was again changed to hydrogen gas (balloon) and the reaction was sealed with balloon and stirred for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a yellow oil which was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I33) (0.120 g, 66% yield) as a yellow foam; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.60 (s, 1H), 7.88-7.77 (m, 2H), 7.61-7.39 (m, 4H), 6.93 (d, J=9.1 Hz, 2H), 3.85 (s, 3H), 3.52-3.42 (m, 4H), 3.21-2.99 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.86 min; m/z 586.3 [M+H]+.