Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:4][C:3]1([CH3:5])[C:10]2[C:9](=[CH:8][CH:7]=[C:6]([OH:12])[CH:11]=2)[CH2:1][CH2:2]1
Reactant: Oc1ccccc1
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(C)CCc2ccc(O)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
322 g of isoprene, stabilized with 1 g of phenothiazine, were added dropwise over the course of 8 hours to a solution of 403 g of phenol, 50 g of 85% strength phosphoric acid and 9 ml of water in 2.14 liters of xylene at 110° C. To complete the reaction, the mixture was stirred overnight at 110° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 230 g of 3,3-dimethyl-5-hydroxy-indane, boiling point 132°-134° C/10 mm Hg; melting point 84.5° -86.5° C. ##STR30##
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Li+]>O1CCCC1>[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CC1CC1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A cooled (−40° C.) solution of cyclopropylacetic acid (5.13 g, 51.250 mmol) in anhydrous tetrahydrofuran (150 mL) was subsequently treated with triethylamine (21.4 mL, 153.75 mmol) and trimethylacetyl chloride (6.9 mL, 56.375 mmol). After stirring at −40° C. for 1 h, the mixture was treated with (S)-4-benzyl-oxazolidin-2-one (9.99 g, 56.375 mmol) and lithium chloride (2.39 g, 56.375 mmol). The mixture was allowed to slowly warm to room temperature and after stirring at room temperature for 22 h, the reaction was partitioned between dichloromethane and half-saturated ammonium chloride. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to afford the title compound (11.63 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.19-0.32 (m, 2H), 0.56-0.69 (m, 2H), 1.10-1.24 (m, 1H), 2.76-2.87 (m, 2H), 2.96 (dd, J=16.9, 6.9 Hz, 1H), 3.34 (dd, J=13.2, 3.3 Hz, 1H), 4.15-4.29 (m, 2H), 4.66-4.77 (m, 1H), 7.20-7.40 (m, 5H). LCMS (m/z) 282.1 [M+Na], Tr=2.78 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]1)(=[O:41])=[O:42]
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)n1cc(C=O)c(C)c1-c1ccccc1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl chloride (298 mg), the title compound was obtained as an oil (yield 379 mg, about 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:27]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.97 g, 3 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.21 g, 3.15 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.7 mmoles).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2nccc(CCl)n2)cc(OC)c1OC
Product: COc1cc(-c2nccc(CN3CCCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)n2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyrimidine (300 mg) and homopiperazine (51 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.FC(F)(F)C(O)=O.C(OCC)C.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(O)(=O)C>[CH:53]1([N:52]=[C:51]=[N:50][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1.[C:51]([NH:50][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)([NH:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:8]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 8 h

Procedure:
30 g. of ribostamycin (the free base form) was added to 127 ml. of trifluoroacetic acid under ice-cooling and stirring, and the mixture was allowed to stand at ambient temperature overnight. The resulting solution of amber color was admixed with 400 ml of ethyl ether, and the admixture was cooled to precipitate 69 g of a salt of ribostamycin with trifluoroacetic acid which was then removed by filtration. A 20 g. portion of this ribostamycin trifluoroacetate was taken and then dissolved in 250 ml of tetrahydrofuran together with 16.4 g. of (S)-α-hydroxy-γ-N-phthalimido-n-butyric acid of the formula ##STR25## The solution was cooled with ice. A solution of 36.4 g of dicylcohexylcarbodiimide in 146 ml of tetrahydrofuran was prepared and cooled with ice. Both the solutions was combined together under ice-cooling and stirring. The combined solutions were agitated at ambient temperature for 2-3 hours and admixed with 8 ml of glacial acetic acid to decompose the excess of dicyclohexylcarbodiimide. 3286 mg of dicyclohexylurea produced was deposited and filtered off. The filtrate was concentrated to dryness, giving 43 g of a pale yellow colored solid comprising mixed trifluoroacetic acid salts of O-((S)-α-hydroxy-γ-N-phthalimido-n-butyryl)-ribostamycins.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C(#N)C>[O:42]=[C:41]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:25]2[CH2:26][CH2:27][C:28](=[O:29])[C:24]=2[CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[NH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (125 μL, 0.89 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-(ethylsulfonyl)benzonitrile hydrochloride (intermediate 20.2, 1.78 g, 3.56 mmol) and 1,1′-carbonyldiimidazole (720 mg, 4.45 mmol) in acetonitrile (20 mL), and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the residue is treated with water (20 mL). The precipitate is filtered and dried. Yield: 1.61 g. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.56 min (X012_801).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1cc(F)ccc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: N#Cc1cc(F)ccc1-c1cccc([N+](=O)[O-])c1

Procedure:
2-Bromo-5-fluorobenzonitrile and 3-nitrophenylboronic acid were coupled following the procedure in Example 1 to afford 4-fluoro-3′-nitro-biphenyl-2-carbonitrile as a black solid: 1H NMR (360 MHz, CDCl3) δ 7.39-7.48 (2H, m), 7.52-7.64 (1H, m), 7.71 (1H, dd, J 8, 8 Hz), 7.89 (1H, d, J 8 Hz), 8.33-8.37 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:3][CH2:4]OC1C=CC=CC=1.[BrH:18]>C(Cl)(Cl)Cl>[BrH:18].[CH3:1][CH:2]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:3][CH2:4][Br:18]
Reactant: CC(CCOc1ccccc1)N1CCCCC1
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC(CCBr)N1CCCCC1
Yield: 75 %

Procedure:
5 g of the 1-(1-methyl-3-phenoxypropyl)piperidine thus obtained was reacted with 30 ml of 40% hydrobromic acid at 150° C. for 7 hours with stirring. The reaction solution was cooled, 20 ml of chloroform was added and then the solution separated into two phases, which phases were then separated from each other. The hydrobromic acid was removed under reduced pressure and the residue was recrystallized from 5 ml of ethyl alcohol to give 4.84 g of 1-(1-methyl-3-bromopropyl)piperidine hydrobromide in a yield of 75%.
Reaction SMILES: [OH-].[Na+].Br[C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>COCCOC.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:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:30]4[CH:29]=[CH:28][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[CH:25][CH:26]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2nc(-c3cccc(Br)c3)n(-c3ccccc3)n2)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: c1ccc(-n2nc(-c3ccc(-c4ccc5ccccc5c4)cc3)nc2-c2cccc(-c3ccc4ccccc4c3)c2)cc1
Temperature: 85 °C
Yield: 36.9 %

Procedure:
Sodium hydroxide solution (0.2 g NaOH dissolved in 5 ml of water) and 0.12 g (0.1 mmol) of Pd(PPh3)4 are added to 0.9 g (1.97 mmol) of the triazole obtained in step A) and 0.82 g (4.7 mmol) of naphthalene-2-boronic acid in 15 ml of 1,2-dimethoxy ethane under a nitrogen atmosphere. The reaction mixture is heated at 85° C. for 24 h, cooled and extracted with ethyl acetate. The organic solvent is removed and the residue is chromatographed. 0.4 g of desired compound A-21 is obtained as greenish solid (yield (40%); mp: 156-158° C.).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=1.Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1>>[F:38][C:39]1([F:43])[CH2:42][N:41]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=2)[CH2:40]1
Reactant: FC1(F)CNC1
Reactant: Cc1ccc(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4F)c3c2)nc1
Agent: Cl
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4F)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting (1S,2R)-2-{1-(4-bromo-2-fluorobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid and 3,3-difluoroazetidine hydrochloride. MS (ESI): mass calcd. for C31H31F3N4O3, 564.23; m/z found, 565.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (5, 1H), 7.67-7.63 (m, 1H), 7.55 (d, J=8.6, 1H), 7.45 (d, J=8.0, 1H), 7.02-6.98 (m, 2H), 6.81 (t, J=8.5, 1H), 6.39 (dd, J=12.3, 2.3, 1H), 6.24 (dd, J=8.4, 2.3, 1H), 5.47 (d, J=16.6, 1H), 5.41 (d, J=16.6, 1H), 5.12 (5, 2H), 4.21 (t, J=12.0, 4H), 3.68-3.54 (m, 1H), 2.91-2.82 (m, 1H), 2.35 (s, 3H), 2.34-2.26 (m, 1H), 2.12-2.02 (m, 1H), 1.90-1.75 (m, 4H), 1.56-1.49 (m, 1H), 1.49-1.42 (m, 1H).
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][P:12]([O:17]CC)([O:14]CC)=[O:13])[C@@H:7]1[C:20]([O:22]CC)=[O:21])=O)C.[ClH:25]>>[ClH:25].[P:12]([CH2:11][CH:8]1[CH2:9][CH2:10][NH:6][CH:7]1[C:20]([OH:22])=[O:21])([OH:14])([OH:17])=[O:13]
Reactant: CCOC(=O)[C@H]1[C@H](CP(=O)(OCC)OCC)CCN1C(=O)OCC
Agent: Cl
Product: O=C(O)C1NCCC1CP(=O)(O)O

Procedure:
A solution of 2.7 g of cis and trans ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl)pyrrolidine-2-carboxylate is heated under reflux with 6N hydrochloric acid for 6 hours to yield 3-(phosphonomethyl)pyrrolidine-2-carboxylic acid hydrochloride; NMR (D2O): 4.78, 4.40, 3.95, 3.83, 3.72, 3.20, 3.01, 2.78, 2.69 ppm.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][O:27][CH3:28])=[O:32]
Reactant: COCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C(C)C
Yield: 80.7 %

Procedure:
A solution of {2-[3-chloro-5-(isopropyl-2-methoxy-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (Intermediate SS8) (0.056 g) and trifluoroacetic acid (0.6 ml) in dichloromethane (0.6 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (94:6:1 then 92:8:1 v/v/v), to give the title compound as a colourless gum (0.036 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[C:26]([CH3:35])=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[C:26]([CH3:35])=[N:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(OC(C)C)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1nc(OC(C)C)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 3-bromo-6-isopropoxy-2-methyl-pyridine (Intermediate 25) in analogy to Example 1a): MS (ISP): 453.2 and 455.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24]C(OC(C)(C)C)=O)[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC(=CC1=2)[Cl:49])=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:69][C:70]1[CH:80]=[CH:79][C:73]([CH2:74][NH:75][CH:76]2[CH2:78][CH2:77]2)=[CH:72][C:71]=1[O:81][CH2:82][CH2:83][CH2:84][O:85][CH3:86].Cl>C(Cl)Cl.CC#N>[ClH:49].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@@H:20]([C:32](=[O:33])[N:75]([CH2:74][C:73]4[CH:79]=[CH:80][C:70]([Cl:69])=[C:71]([O:81][CH2:82][CH2:83][CH2:84][O:85][CH3:86])[CH:72]=4)[CH:76]4[CH2:78][CH2:77]4)[CH2:21][C@@H:22]([NH2:24])[CH2:23]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COCCCOc1cc(CNC2CC2)ccc1Cl
Reactant: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (1.78 g, 3.82 mmol), HCTU (1.75 g, 4.23 mmol) and DIPEA (265.3 μl, 1.55 mmol) in a 1:1 mixture of CH2Cl2/CH3CN (20 ml) is stirred for 10 min at RT. After cooling to 5° C., [4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-amine (1.04 g, 3.86 mmol) is added in one portion. The ice-bath is removed and the mixture stirred for 14 h at RT. The reaction mixture is diluted with ethyl acetate and washed twice with K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude oil thus obtained is stirred with HCl (5M in 2-propanol, 12 ml, 60 mmol) for 1 h and then evaporated to afford the title compound as a yellow oil. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.31 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29][CH2:28]CC[C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.[Cl:31]C1C=C(C2N3C(=CC=N3)N=C3C=2CCC3)C=CC=1OCCCCl.C[C@@H]1CCCN1>>[Cl:31][C:12]1[CH:13]=[C:14]([C:17]2[N:18]3[C:22](=[CH:21][CH:20]=[N:19]3)[N:23]=[C:24]3[C:25]=2[CH2:28][CH2:29][CH2:30]3)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1Cl
Agent: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1Cl

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[(3-chloro)-4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 2-(R)-methyl-pyrrolidine provided the title compound.
Reaction SMILES: [I-].[K+].Cl[CH2:4][C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.C[NH:27]C1CC1.O1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:34]1([CH2:35][NH:27][CH2:4][C:5]2[N:9]3[C:10]4[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=4[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])=[N:13][CH2:14][C:8]3=[N:7][N:6]=2)[CH2:32][CH2:33]1
Reactant: C1CCOC1
Reactant: CNC1CC1
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Product: Clc1ccccc1C1=NCc2nnc(CNCC3CC3)n2-c2ccccc21

Procedure:
In the manner given in Example 2, potassium iodide and 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([NH:17][C:18]([C:20]3([C:23]4[CH:33]=[CH:32][C:26]5[O:27][C:28]([F:31])([F:30])[O:29][C:25]=5[CH:24]=4)[CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:34])=[CH:5]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(N(CC)CC)C>CN(C)C=O>[F:30][C:28]1([F:31])[O:27][C:26]2[CH:32]=[CH:33][C:23]([C:20]3([C:18]([NH:17][C:15]4[N:16]=[C:11]([C:6]5[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH2:3][CH2:2][NH:1][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH:5]=5)[C:12]([CH3:34])=[CH:13][CH:14]=4)=[O:19])[CH2:22][CH2:21]3)=[CH:24][C:25]=2[O:29]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CCN)c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a flask containing N-(6-(1-(2-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (36 mg, 0.08 mmol), ethyl chloroformate (10 mg, 0.09 mmol), and triethylamine (32 μL, 0.23 mmol) was added N,N-dimethyl formamide (1 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse-phase preparative liquid chromatography to give the product (11 mg, 25%). ESI-MS m/z calc. 540.18. found 541.7 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[N:32][C:33]=1[CH:34]1[CH2:36][CH2:35]1.COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[NH2:37][C:30]1[CH:29]=[C:28]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:26])[CH:8]=2)[C:33]([CH:34]2[CH2:36][CH2:35]2)=[N:32][CH:31]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: Nc1cnc(C2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 130 °C
Yield: 85 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (150 mg, 0.42 mmol) and 5-bromo-6-cyclopropylpyridin-3-amine (180 mg, 0.84 mmol) were added to a solvent mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL). To the mixture were added PEPPSI-Ipr (29 mg, 0.03 mmol) and Cs2CO3 (413 mg, 1 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 129 mg of 4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.