Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[C:15](Br)[CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1.C(=O)(O)[O-].[Na+]>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.COCCOC>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[C:15]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH3:24])=[N:31][CH:30]=3)[CH:14]=[C:13]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(-c2nc(Br)cc(N3CCOCC3)n2)c1
Reactant: COc1ncc(B(O)O)cn1
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
Product: COc1ncc(-c2cc(N3CCOCC3)nc(-c3cccc(NC(C)=O)c3)n2)cn1
Temperature: 60 °C
Yield: 85.3 %

Procedure:
A mixture of 2-(3-acetamidophenyl)-4-bromo-6-morpholinopyrimidine (0.037 g), 2-methoxypyrimidin-5-ylboronic acid (0.019 g), tetrakis(triphenylphosphine)palladium(0) (3 mg), a saturated aqueous sodium bicarbonate solution (0.2 ml) and 1,2-dimethoxyethane (2 ml) was stirred and heated to 60° C. for 18 hours under an atmosphere of nitrogen. A second portion of each of 2-methoxypyrimidin-5-ylboronic acid (0.019 g), tetrakis(triphenylphosphine)palladium(0) (2 mg), a saturated aqueous sodium bicarbonate solution (0.2 ml) and 1,2-dimethoxyethane (1 ml) was added and the resultant mixture was heated to 60° C. for a further 18 hours. The resultant reaction mixture was evaporated and the residue was triturated under a 5:1 mixture (1 ml) of methylene chloride and methanol. The soluble material was purified by column chromatography on reversed-phase silica using an ‘Isolute SCX’ column (1 g; International Sorbent Technology Limited, Mid Glamorgan, UK) by initially washing the column with methanol (5 ml) followed by elution with a 5:3:2 mixture of methanol, methylene chloride and a 7M methanolic ammonia solution. The material so obtained was dried under vacuum. There was thus obtained the title compound as a solid (0.034 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 3.66-3.8 (m, 8H), 3.97 (s, 3H), 7.3-7.37 (m, 2H), 7.82 (d, 1H), 8.03-8.09 (m, 1H), 8.52 (s, 1H), 9.38 (s, 2H), 9.98 (s, 1H); Mass Spectrum: M+H+407.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9][N:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1CCOCC1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCOCC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(tetrahydro-pyran-4-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].Br[C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([C:3]1[CH:4]=[C:5]([C:22]2[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=2)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: N#Cc1cc(B(O)O)cc(F)c1OCc1ccccc1
Reactant: COC(=O)c1ccc(Br)s1
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: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)s1

Procedure:
(3-Cyano-4-benzyloxy-5-fluorophenyl)boronic acid and methyl 5-bromothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 2 M aqueous sodium carbonate solution and the whole was heated and refluxed for 3 hours in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 5-(3-cyano-4-benzyloxy-5-fluorophenyl)thiophene-2-carboxylate. F: 368.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1ccccn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.6 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 0.84 mL (8.4 mmol) 2-ethynyl-pyridine using 106 mg (0.57 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 7.8 mL (56 mmol) triethylamine in 10 mL dry DMF. Additional amounts are added after 24 h and 48 h reaction time, respectively. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 2.0 g (>100%, approximately 70% pure).
Reaction SMILES: C[CH:2]([S:4](Cl)(=[O:6])=[O:5])C.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[CH2:30][CH2:29][N:28]([S:4]([CH3:2])(=[O:6])=[O:5])[CH2:27]4)=[CH:24][CH:25]=3)=[CH:13][C:12]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: CS(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 557C, substituting methane sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (t, J=5.9 Hz, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.88 (m, 3H), 7.52 (d, J=1.2 Hz, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 3.73 (dd, J=9.6, 7.5 Hz, 1H), 3.47 (m, 2H), 3.35 (m, 1H), 3.19 (t, J=9.6 Hz, 1H), 2.97 (s, 3H), 2.31 (m, 1H), 2.02 (m, 1H); MS (ESI(+)) m/e 399 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27](Br)[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Yield: 41.2 %

Procedure:
A mixture of N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-bromo-4-fluoro-benzamide (126 mg, 0.24 mmol) (D3), caesium carbonate (117 mg, 0.36 mmol), 2-pyrrolidinone (1 ml of 0.36M solution in 1,4-dioxan, 0.36 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1 ml of 0.015M solution in 1,4-dioxan) and tris(dibenzylideneacetone)dipalladium (0) (1 ml of 0.005M solution in 1,4-dioxan, 0.01 mmol of Pd) was refluxed under argon for 40 h. After cooling, the mixture was filtered and evaporated in vacuo. Column chromatography on silica gel (elution with dichloromethane/methanol) gave the title compound (52 mg) as a white solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:34]1[CH:38]=[C:37]([CH2:39][OH:40])[CH:36]=[N:35]1.[F:41][C:42]1[CH:49]=[C:48](O)[CH:47]=[CH:46][C:43]=1[C:44]#[N:45]>O1CCCC1>[F:41][C:42]1[CH:49]=[C:48]([O:40][CH2:39][C:37]2[CH:36]=[N:35][S:34][CH:38]=2)[CH:47]=[CH:46][C:43]=1[C:44]#[N:45]
Reactant: OCc1cnsc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2cnsc2)cc1F
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
Diisopropyl azodicarboxylate (1.19 g) is added to a stirred solution of triphenylphosphine (1.55 g) in tetrahydrofuran (30 mL) at 0° C. under nitrogen and stirring is continued at 0° C. for 30 minutes. A solution of isothiazol-4-ylmethanol (0.34 g) and 2-fluoro-4-hydroxybenzonitrile (0.4 g) in tetrahydrofuran (30 mL) is added at such a rate that the temperature did not exceed 0° C. After the addition is complete stirring is continued at 0° C. for 30 minutes then at ambient temperature for 24 hours. The reaction mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed with water (50 mL), with brine (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated to give 2-fluoro-4-(isothiazol-4-ylmethoxy)benzonitrile (0.24 g), m.p. 102-105° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)CCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCCO
Solvent: CCCCO
Product: Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Yield: 33 %

Procedure:
A mixture of 171 parts of 1-chloro-4-methyl-2-nitrobenzene, 150 parts of 3-amino-1-propanol and 400 parts of butanol is stirred and refluxed for 30 hours. The reaction mixture is evaporated and the residue is poured onto water. The product is extracted with methylbenzene. The extract is washed with water and with a hydrochloric acid solution 2N, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 70 parts (33%) of 3-[(4-methyl-2-nitrophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)Cl>[C:32]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5]1)(=[O:34])[CH3:33]
Reactant: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Example 101, 67 mg, 0.199 mmol) in DCM (2 mL) was added triethylamine (55 μL, 0.395 mmol) and then acetyl chloride (21 μL, 0.295 mmol). The reaction mixture was stirred at room temperature for 30 minutes under argon atmosphere. Water (2 mL) was added, and the mixture poured onto a hydrophobic cartridge. The heavier organic phase was concentrated under vacuum to leave white crystals. Purification by MDAP left a white solid, 4-{5-[(4-acetyl-1-piperazinyl)methyl]-1H-tetrazol-1-yl}-2-(trifluoromethyl)benzonitrile (48 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[S:55]1[CH:59]=[CH:58][N:57]=[C:56]1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:56]2[S:55][CH:59]=[CH:58][N:57]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2nccs2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 8.00 (m, 2H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 5.20 (m, 1H), 4.48 (m, 1H), 3.22 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.25 (m, 2H). LCMS for C28H28ClN8O2S (M+H)+: m/z=575.2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1.[C-]#N.[Na+]>O.CO>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 1,4-benzodioxan-6-amine (170 mg, 1.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (206 mg, 1.2 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) and stirred at room temperature for 20 minutes. Work-up and purification afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine as a white solid (245 mg, 71% over 2 steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1
Yield: 91.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol), 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), and n-BuOH was heated at reflux for 3 h. The mixture was concentrated and the residue treated with H2O (150 mL) and EtOAc (175 mL). The EtOAc phase was separated, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated to give the title compound (4.5 g) which was used without further purification. 1H NMR (DMSO-d6) δ 8.29 (s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.90 (d, 2H, J=8.2 Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:11]2[N:10]([C@@H:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:13]([OH:17])[CH2:14][NH:15][CH3:16])[C:9](=[O:24])[N:8]([CH:25]([CH3:27])[CH3:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC1C2N([C@@H](C3C=CC=CC=3)[C@H](O)CO)C(=O)N(C(C)C)C=2C=CC=1>>[ClH:1].[F:2][C:3]1[C:11]2[N:10]([CH:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]([OH:17])[CH2:14][NH:15][CH3:16])[C:9](=[O:24])[N:8]([CH:25]([CH3:27])[CH3:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CNC[C@@H](O)[C@H](c1ccccc1)n1c(=O)n(C(C)C)c2cccc(F)c21
Agent: CC(C)n1c(=O)n([C@@H](c2ccccc2)[C@H](O)CO)c2c(F)cccc21
Agent: Cl
Product: CNCC(O)C(c1ccccc1)n1c(=O)n(C(C)C)c2cccc(F)c21

Procedure:
In an analogous manner to EXAMPLE 192, step 4 4-fluoro-3-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from 4-fluoro-3-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m/z 358.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:15][C:9]=3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1.CO.[OH-].[K+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:21])[C:17]([OH:19])=[O:18])=[CH:15][C:9]=3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc(N)ccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(N)ccc1S2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.6 %

Procedure:
To a mixture of 78 mg of methyl 2-(8-amino-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate and 3 ml of methanol was added with ice cooling 200 mg of potassium hydroxide in 3 ml of water, and the resulting mixture was stirred at room temperature for 6 hours. After filtrating the reaction mixture to remove insoluble substances, the filtrate was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellow solid substance, which was chromatographed over 2 g of silica gel and eluted with chloroform/methanol (50/1), and there were obtained yellow crystals. The thus obtained crystals were recrystallized from chloroform-methanol to obtain 49 mg (yield: 75%) of 2-(8-amino-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 189°-191° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])=[O:23])[CH2:17][CH2:16]1.[OH-:33].[NH4+]>O>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH:13]([OH:33])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:32])=[O:23])[CH2:19][CH2:20]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CCC2COc3ccccc3O2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
A solution of 3.5 g of 1-[2-(1,4-benzodioxan-2-yl)ethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt in water (50 ml) is adjusted to pH 12 with ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride is evaporated to afford 3 g of 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as the free base.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(NC1C2N=CN(C=2N=CN=1)[C@@H]1O[C@H](CO[C:49]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C@@H](O)C1)(=O)C1C=CC=CC=1>>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([C:49]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@@H:2]([F:1])[C@@H:6]2[OH:7])([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)=[CH:63][CH:62]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F)c1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared from 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-N6 -benzoyladenine by the same procedure used for the preparation of N6 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1>>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([CH2:32][CH:30]2[CH2:29][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:31]2)=[CH:34]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: c1ccc2c(CC3CNC3)c[nH]c2c1
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccccc24)C1)O3

Procedure:
This compound was prepared as described for Example 1, using (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.26 g, 0.59 mmol), 3-azetidin-3-ylmethyl-1H-indole (0.11 g, 0.59 mmol), to afford 0.035 g of the (S)-enantiomer of the title compound as a light brown foam. 1H NMR (500 MHz, DMSO-D6): δ 2.74-2.82 (m, 3H), 2.90 (d, J=7.5 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.03 (t, J=6.6 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 4.08 (m, 1H), 4.30-4.32 (m, 1H), 4.37 (m, 1H), 6.94-6.97 (m, 1H), 7.04-7.08 (m, 2H), 7.30-7.36 (m, 3H), 7.42 (d, J=9.1Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H).