Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis-(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, waiter and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:methyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([Cl:15])=[O:9]
Reactant: O=C(O)CCSCCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCSCCC(F)(F)F
Temperature: 36 °C
Yield: 86 %

Procedure:
A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogen inlet, reflux condenser, and thermometer, was charged with 3-((3,3,3-trifluoropropyl)thio)propanoic acid ((188 g, 883 mmol) in dichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) was then added dropwise over 50 minutes. The reaction mixture was heated to reflux (about 36° C.) for two hours, then cooled to room temperature. Concentration under vacuum on a rotary evaporator, followed by distillation (40 Torr, product collected from 123-127° C.) gave the title compound as a clear colorless liquid (177.3 g, 86%): 1H NMR (400 MHz, CDCl3) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67 (m, 2H), 2.48-2.31 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −66.42, −66.43, −66.44, −66.44.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.C([Sn](C#[C:44][Si:45](C)([CH3:47])[CH3:46])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH:21]1([N:7]2[C:8]3[C:3](=[C:2]([Si:45]([CH3:47])([CH3:46])[CH3:44])[C:11]([F:12])=[C:10]([N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[C:9]=3[F:20])[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]2)[CH2:23][CH2:22]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c(Br)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c([Si](C)(C)C)c2c1=O
Yield: 58.1 %

Procedure:
1.1 g of ethyl 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate, 1.2 g of tributylstannyl-trimethylsilylacetylene and 0.135 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 3 hours in 10 ml of absolute toluene. The reaction mixture is treated with a further 5 ml of toluene and filtered while hot. The product crystallizes out of the filtrate. After filtration with suction and drying, 0.63 g of the title compound is obtained (56% of theory).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][O:12][C:13]1[CH:59]=[CH:58][C:16]([CH2:17][N:18]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:26]4[CH2:39][CH2:38][N:37]([C:40]5[CH:48]=[CH:47][C:43]([C:44]([OH:46])=O)=[CH:42][CH:41]=5)[C:27]=4[N:28]=[C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:30]=3)=[CH:21][N:20]=2)=[CH:15][CH:14]=1>>[CH3:57][O:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][N:18]([CH2:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:59][CH:58]=2)[C:19]2[N:20]=[CH:21][C:22]([C:25]3[C:26]4[CH2:39][CH2:38][N:37]([C:40]5[CH:48]=[CH:47][C:43]([C:44]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)=[O:46])=[CH:42][CH:41]=5)[C:27]=4[N:28]=[C:29]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[N:30]=3)=[CH:23][N:24]=2)=[CH:51][CH:52]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CNCCN1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)CCN4CCOCC4)cc3)cn2)cc1
Yield: 86.7 %

Procedure:
Using methyl-(2-morpholin-4-yl-ethyl)-amine (29.8 mg, 0.206 mmol) obtained in Step A instead of 3-(aminomethyl)pyridine, and 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (68.1 mg, 0.103 mmol) obtained in Step A in Example 1-D-19, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-methyl-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (70.2 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-139) as a yellow powder (42.0 mg, 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].[NH2:8][CH2:9][C@H:10]([CH3:38])[O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:25]([Cl:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2>>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[CH:21][C:12]=3[O:11][C@@H:10]([CH3:38])[CH2:9][NH:8][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[N:17]=[CH:16][N:15]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN(C)CC(=O)O
Product: C[C@@H](CNC(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 49 %

Procedure:
The procedure described in Example 1 was repeated using N,N-dimethylglycine and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 49% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.07 (s, 6H), 2.80 (s, 2H), 3.41 (m, 1H), 3.73 (m, 1H), 4.93 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.35 (t, 1H), 7.59 (m, 2H), 7.70 (t, 1H), 7.86 (td, 1H), 8.12 (m, 2H), 8.47 (s, 1H), 8.58 (d, 1H), 9.96 (s, 1H); Mass Spectrum MH+ 521.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](CCCC(O)=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:22][CH2:23][CH2:24][C:25]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])=[O:26])=[CH:29][CH:28]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Ile-OtBu HCl (45 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.81-12.98 (br.s, 1 H), 8.95 (s, 1 H), 7.93 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.88 (d, 4 H), 4.19 (dd, 1 H), 4.05 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.53 (t, 2 H), 2.39 (s, 3 H), 2.18 (m, 2 H), 1.76 (m, 3 H), 1.39 (m, 1 H), 1.20 (m, 1 H), 0.83 (m, 6 H); MS (APCI+) m/z 673 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[N:18](C(OC(C)(C)C)=O)[C:17](=[O:26])[O:16][C:15]([CH3:28])([CH3:27])[C:14]=2[CH:29]=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]([CH3:9])[C:3]=1[C:10]1[CH:11]=[CH:12][C:13]2[NH:18][C:17](=[O:26])[O:16][C:15]([CH3:27])([CH3:28])[C:14]=2[CH:29]=1
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 80 °C
Yield: 54.2 %

Procedure:
A solution of tert-butyl 6-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-1(4H)-carboxylate (1 eq, 0.4 g, 0.87 mmol) in THF was added to a solution of sodium ethoxide (3 eq, 0.18 g, 2.6 mmol) in ethanol (10 mL). The solution was heated at 80° C. for 1 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 4N HCl (10 mL) was added. After heating to 60° C. for 16 h the solution was cooled, poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The product, 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3, 1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.17 g, 54%) was obtained by crystallization from 20% ethyl acetate/hexane. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 3.62 (s, 3H), 7.02 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.35 (dd, 1H, J=1.3, 8.2 Hz), 7.40 (s, 1H), 10.47 (s, 1H). MS (ESI (−)) m/z 358/360 (M−H)−. Anal. calcd for C16H14N3O2Br, C, 53.4, H, 3.92, N, 11.7. Found, C, 52.6, H, 3.82, N, 11.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9].Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(OC)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 16 g (0.082 mol) of methyl 3-methoxy-4-hydroxyphenylacetate, 14.5 g (0.082 mol) of 2-chloromethylquinoline and 3.28 g (0.082 mol) of sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: [H][H]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
2,3-Dichloro-6-nitroaniline (20.11 g, 97.14 mmol), Raney nickel (Aldrich, Milwaukee, slurry in water, 4.78 g wet), and ethanol (250 mL) were combined in an autoclave which was presssurized to 150 psig with hydrogen. The resulting reaction mixture was allowed to stir at rt overnight. The mixture was then filtered through a pad of Celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to leave a dark brown solid. The solid was slurried in hexanes and was collected on a Büchner funnel to afford 16.31 g (95%) of a brown solid. MS (EI): m/z 177.0 (M+H); 1H NMR (DMSO-d6) δ: 6.60 (d, J=8.3 Hz, 1H, ArH), 6.49 (d, J=8.4 Hz, 1H, ArH), 4.98 (br s, 4H, overlapping NH2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[N:4]=1)#[N:2].N.[H][H]>[Ni].C(O)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[N:4]=1
Reactant: [H][H]
Reactant: N#Cc1cccc(Cl)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cccc(Cl)n1
Yield: 94.4 %

Procedure:
A 3.3 g portion of Raney nickel was suspended in 30 ml of ethanol, and the suspension was mixed with 1.42 g of 2-cyano-6-chloropyridine and 10 ml of 28% aqueous ammonia and stirred at room temperature for 4 hours in a stream of hydrogen. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain 1.38 g of the title compound as a mixture.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Br)cc1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(NCc1cccnc1)c1ccc(Br)cc1

Procedure:
A solution of 4-bromo-α-methylbenzylamine (1.5 g, 7.7 mmol), 3-pyridinecarboxaldehyde (0.8 g, 7.5 mmol), and sodium triacetoxyborohydride (2.25 g, 10.5 mmol) in 60 ml of 1,2-dichloroethane was stirred at room temperature for 18 h. The solution was diluted with dichloromethane and washed twice with a saturated sodium bicarbonate solution, once with water, and once with brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 8.70 (m,2H), 7.85 (m,1H), 7.67 (d,2H,J=8 Hz), 7.45 (d,2H,J=8 Hz), 7.43 (m,1H), 3.95 (q,1H,J=8 Hz), 3.83 (q,ABX,2H), 1.57 (d,3H,J=8 Hz). MS calcd. 291.2; MS (M+1) 292.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[N:21]([CH2:14][C@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]1[OH:20])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
To a solution of cis-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine (4.44 g) in dimethylformamide (60 ml) were added sodium azide (1.4 g) and ammonium chloride (1.15 g), and the resulting mixture was stirred at 60° C. for 6 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 3.4 g of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: C1CSCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCSC1

Procedure:
Following General Procedure C and using N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl3/MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][C@H:32]([CH3:34])[C@@H:31]([OH:35])[C@H:30]([NH:36]C(=O)OC(C)(C)C)[CH2:29]3)=[C:20]3[CH2:26][CH2:25][CH:24]([OH:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:44].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:36][C@H:30]1[C@H:31]([OH:35])[C@@H:32]([CH3:34])[CH2:33][N:28]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:44])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH:24]([OH:27])[CH2:25][CH2:26][C:20]=23)[CH2:29]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6 mg, 0.01 mmol) and TFA in DCM (4.0 M; 2.0 mL, 8.0 mmol) was stirred at room temperature for 1 h. After removal of the solvent, the residue was then diluted with MeOH (4 mL) and NH4OH solution (0.5 mL) and filtered. The filtrate was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give two diastereoisomers of the title compound as a white powders.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33](OS(C(F)(F)F)(=O)=O)=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1.[H][H]>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1ccc(OS(=O)(=O)C(F)(F)F)c2c1C1CCC2C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1cccc2c1C1CCC2C1

Procedure:
To a solution of EXAMPLE 546D (80 mg) in tetrahydrofuran and methanol (40 ml, 1:1) was added 10% palladium hydroxide (40 mg). The mixture was shaken under 30 psi of hydrogen for 4 hours. The catalyst was filtered off, the filtrate was concentrated and the residue was hydrolyzed with LiOH/tetrahydrofuran/methanol/H2O. The product was purified by reverse phase HPLC.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:37])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:37][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:24]3)[N:16]=[C:15]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methanesulfonyl chloride (0.07 mL, 0.904 mmol) was added drop-wise to a mixture of the above amine (102 mg, 0.229 mmol) and powdered K2CO3 (253 mg, 1.83 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and allowed to warm to room temperature. After 5 hrs, additional K2CO3 (127 mg, 0.919 mmol) and methanesulfonyl chloride (0.04 mL, 0.517 mmol) were added and the mixture stirred at room temperature for another 16 hrs. Water was added and the layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole (73 mg, 61%): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (CDCl3) δ 8.00 (dd, J=8.4, 0.6 Hz, 1H), 7.55 (t, JHF=53.5, 1H), 7.40 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.14-4.09 (m, 6H), 4.06 (s, 3H), 3.56 (m, 2H), 3.37 (br s, 4H), 2.96 (m, 1H), 2.83 (s, 3H), 1.99 (ddd, J=12.1, 7.9, 4.0, 4H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.4; N, 18.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:22][C:15]3([CH2:20][CH2:19][N:18](C)[CH2:17][CH2:16]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:22][C:15]3([CH2:16][CH2:17][N:18]([C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[CH2:19][CH2:20]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)SC(c1ccc(F)cc1)c1ccccc12
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccc(F)cc1)c1ccccc12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 3-(4-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 27 (3.6 g), 2.1 g of phenyl chloroformate in 100 ml of CH2Cl2 is stirred at room temperature for 64 hours. The solution is washed with 10% aqueous NaOH, water, and dried over MgSO4. Evaporation under reduced pressure affords a crystalline residue, m.p. 198°-200° C. Recrystallization of the crude product from acetone-pentane gives granular crystals, m.p. 200°-201° C. of 3-(4-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:26]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Cc1ccncc1I
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccncc1C12CCCN1CCC2
Temperature: -95 °C
Reaction time: 2 h
Yield: 6.5 %

Procedure:
3-Iodo-4-methylpyridine (330 mg, 3.10 mmol) was dissolved in Et2O and cooled to -95° C. A solution of t-BuLi (1.7M in pentane, 4.0 ml, 6.80 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (960 mg, 4.60 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (41 mg, 6%): 1H NMR (CDCl3, 300 MHz) δ1.54-1.69 (m, 2H), 1.77-1.89 (m, 2H), 1.93-2.11 (m, 4H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 3.08-3.15 (m, 2H), 7.02 (d, J=4.8 Hz, 1H), 8.32 (d, J=4.8 Hz, 1H), 9.06 (s, 1H); MS (CI/NH3) m/z: 203 (M+H)+.