Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.[OH-].[Na+]>[C:14]([NH:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CC1CCCCC1)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(CC1CCCCC1)P(O)O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 7.00 g (0.037 moles) of 1-amino-2-cyclohexylethylphosphonous acid in 105 ml of dioxane and 40 ml of 1N NaOH was cooled to 0° C. in an ice bath and stirred vigorously while 10.50 ml (12.53 g; 0.073 moles) of benzyl chloroformate and 80 ml of 1N NaOH were added rapidly and simultaneously over a period of approximately 1 minute. The pH was adjusted to the 8-9 range using 1N NaOH (hydrion paper) added in small increments. The reaction mixture was allowed to come to room temperature, and vigorous stirring was continued for 48 hours. The dioxane was removed in vacuo and the aqueous washed with 100 ml of ether. The ether layer was discarded and the aqueous solution acidified using 1N KHSO4 to approximately pH=1-2 (hydrion paper). The solution was extracted with 5×100 ml of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford N-CBZ-1-amino-2-cyclohexylethylphosphonous acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.[OH-].[Na+].[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)=[O:33])=[CH:30][CH:29]=1
Reactant: BrCC1OCCO1
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(CC1OCCO1)C(=O)c1ccc(CCl)cc1
Temperature: 80 °C
Reaction time: 96 h
Yield: 47.9 %

Procedure:
In an atmosphere of argon, a mixture consisting of o-anisidine (500 mg, 4.06 mmol), triethylamine (1.6 ml, 11.5 mmol) and 2-bromomethyl-1,3-dioxolan (0.96 ml, 8.18 mmol) was stirred at 80° C. for 4 days, dissolved in methylene chloride (8 ml) and then, with cooling in an ice bath, mixed with 20% sodium hydroxide aqueous solution (4 ml) and 4-chloromethylbenzoyl chloride (768 mg, 4.06 mmol). After 1 hour of stirring at the same temperature, the resulting mixture was extracted with methylene chloride, washed with 10% citric acid aqueous solution and saturated brine and then dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ethyl acetate:hexane=2:5) to obtain 704 mg (47.9%) of the title compound in the form of colorless solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[C:28](O)(=[O:30])[CH3:29]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:30])[CH3:29])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (30 mg, 41%), MS (ISP) m/z=371.3 [(M+H)+], mp 157° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and acetic acid.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(O)C>[CH2:1]([CH:15]([C:16]([CH3:18])=[O:17])[C:14]([O:20][CH2:21][CH3:22])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCI
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCC(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-(n-undecyl)-acetoacetate was prepared from undecyl iodide (26.6 .g) by reaction with an equivalent amount of the sodium derivative of ethyl acetoacetate in ethanol (5 hours, reflux temperature). After cooling the solvent is removed on a rotary evaporator, 300 ml of hexane is added to the residue, and the precipitate of salt is now easily filtered. The product is of sufficient purity (g.c-m.s.) to dispense with further work-up. Reaction of it (6.80 g) with 3.5-difluoroaniline (3.1 g) and 0.30 g of p-toluenesulfonic acid monohydrate in 100 ml of benzene (water separator, 3 days) produced the anilinocrotonic ester with very little of the starting materials left. After removal of the solvent, the crude product was added quickly to 30 ml of boiling Dowtherm A and kept at boiling temperature for about 10 minutes. The product crystallizes out upon cooling and is isolated by filtration and washing with hexane (50 ml).
Reaction SMILES: [CH2:1]([Li])CCC.Br[C:7]1[C:19]([F:20])=[C:18]([F:21])[C:10]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:22])[C:8]=1[F:23].Cl[CH2:25][C:26]([Cl:28])=[CH2:27].[Cl-].[NH4+]>O1CCCC1.O>[Cl:28][C:26](=[CH2:27])[CH2:25][C:7]1[C:8]([F:23])=[C:9]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:1][CH2:15][O:14]2)=[C:18]([F:21])[C:19]=1[F:20]
Reactant: Fc1c(F)c(COC2CCCO2)c(F)c(F)c1Br
Reactant: C=C(Cl)CCl
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(Cl)Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5 M in hexane, 2.3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]tetrahydrofuran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained between -30° C. and -20° C. After 15 minutes, copper (I) bromide-dimethyl sulphide complex (1.2 g) was added in one portion and the reaction temperature was maintained at -10° C. for 1 hour, after which time 1,2-dichloroprop-2-ene (1 cm3) was added, the reaction temperature then being allowed to warm to +15° C. After 3 hours, water followed by saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted into diethyl ether. The organic layer was then washed with water and brine, dried, and the solvent evaporated under reduced pressure. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 30°-40° C.) containing diethyl ether (10% by volume) to give 2-[4-(2-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (1.5 g).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].CN(C)CCCN(C)C.[NH2:23][C:24]1[N:29]=[C:28]([OH:30])[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:30][C:28]1[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:47])[CH3:48])([CH3:44])[CH3:45])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=[C:24]([NH2:23])[N:29]=1)(=[O:11])=[O:10]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)CCCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95.4 %

Procedure:
2-Mesitylenesulfonyl chloride (4.96 g, 22.7 mmol) was added to a solution of N,N,N′,N′-tetramethyl-1,3-propanediamine (3.79 mL, 22.7 mmol) and the product of example 8 step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at RT for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried and concentrated. The residue was purified via chromatography on silica to give 8.87 g of the subtitle compound as a white solid; 1H NMR (CDCl3); 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d), 6.33 (1H, dd), 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m), 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93-2.01 (2H, m), 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z 616.
Reaction SMILES: [BrH:1].[O:2]1[CH2:13][CH:3]1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>>[Br:1][CH2:13][CH:3]([OH:2])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: Br
Reactant: CCOP(=O)(CC1CO1)OCC
Product: CCOP(=O)(CC(O)CBr)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
(1)-(a) 47% Aqueous hydrobromic acid (82.8 g) was added dropwise to diethyl 2,3-epoxypropylphosphonate (77.6 g) under ice-cooling and with stirring over a five minutes interval. After the stirring was continued for an hour under ice-cooling and for 3 hours at ambient temperature, the reaction mixture was extracted with ethyl acetate (500 ml). The ethyl acetate layer was separated, washed three times with saturated aqueous sodium bicarbonate solution (200 ml and 100 ml×2) and twice with saturated aqueous sodium chloride solution (100 ml×2), dried over magnesium sulfate and evaporated to dryness to give oily diethyl 3-bromo-2-hydroxypropylphosphonate (94.7 g)
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cc3ccccc3s2)Cc2ccccc2C1
Yield: 69.5 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-2-carboxylic acid (518 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and the DIPEA (0.95 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 110 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.54 g of an off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 10 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 13 through 27 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.62 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=1[O:30][C:29]([CH3:32])=[CH:28][C:27]3=[O:33])[C:7]([C:15]([O:17]CCC#N)=[O:16])=[C:8]([CH3:14])[NH:9]2)[CH3:2].[OH-].[Na+].C(OCC)C>COCCOC.O>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=1[O:30][C:29]([CH3:32])=[CH:28][C:27]3=[O:33])[C:7]([C:15]([OH:17])=[O:16])=[C:8]([CH3:14])[NH:9]2)[CH3:2]
Reactant: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
270 mg (0.61 mmol) of the compound from Example 32A are dissolved in 15 ml of 1,2-dimethoxyethane/water (2:1 v/v), 1.21 ml (1.21 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for 1 h. 30 ml of diethyl ether are then added to the reaction mixture. The aqueous phase is separated off and acidified with 1 N hydrochloric acid. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in vacuo at 40° C. results in 167 mg (70% of theory) of the title compound.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:8])(C)(C)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43]C(O)=O)[CH:40]=[CH:39][C:37]=2[N:38]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)CCl>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][C@H:10]3[CH2:14][O:15][CH:16]3[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]3)=[O:8])[CH:40]=[CH:39][C:37]=2[N:38]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.2 %

Procedure:
In methylene chloride (20 ml), EDC(HCl (691 mg, 3.6 mmol) was added at 0° C. to methyl 4-(1-(tert-butoxycarbonyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylate (580 mg, 2.4 mmol), 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (678 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol) and triethylamine (1.0 ml, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. Ice water (10 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous citric acid solution and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (1:2, v/v) eluate fractions, the title compound (500 mg, 48%) was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.CO>C(Cl)Cl.C(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20](=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCN2CCN(c3cccccc3=O)CC2)cc1OC
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Product: O=c1cccccc1N1CCN(CCc2ccc(O)c(O)c2)CC1
Reaction time: 4 h

Procedure:
A solution of 2-[4-[2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (1.10 g, described in Example 4) in methylene chloride (5 ml) was cooled to -65° C. in dry ice bath. A solution of boron tribromide (3.36 g) in methylene chloride (5 ml) was added dropwise to the solution of the compound. After the addition, the temperature was allowed to rise to room temperature. After 4 hr, the mixture was cooled in an ice bath and methanol (20 ml) was added dropwise. The resulting mixture was slowly brought to reflux and the solid was allowed to dissolve. The solution was then concentrated to the point at which crystals start to separate. Some diethyl ether was added, the mixture was cooled overnight, and filtered to give crude product (1.4 g). Recrystallization form methanol gave the hydrobromide salt (0.5 g) of the title compound: mp 256°-258° C.; ir(nujol) 3490, 2540 and 1522 cm-1 ; uv max(MeOH) 342 (ε=7820), 250 (ε=10720) and 222 nm(ε=11535); nmr(DMSO-d6)δ3.25 (m, 12H), 6.8 (m, 7H) and 8.7 (broad, 2H); and Anal. Calcd for C19H22N2O3.HBr: C, 56.02% H, 5.69% N, 6.88% and Found: C, 55.91% H, 5.74% N, 6.86%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[O:28][CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:27]([O:28][CH3:29])=[O:30])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
Methyl 2-(4-chlorophenyl)piperidine-4-carboxylate (3.13 g, 12.34 mmol) was dissolved in DCM (50 mL), then DIPEA (5.39 mL, 30.84 mmol) was added. Methyl carbonochloridate (1.360 mL, 17.27 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 3 h. The mixture was washed with 0.1 M HCl (2*100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(4-chlorophenyl)piperidine-1,4-dicarboxylate (3.97 g, quant.) as an orange oil. MS m/z 312 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:3]=1.[Si]([N:25]=[N+:26]=[N-:27])(C)(C)C>C1(C)C=CC=CC=1>[N:18]1[NH:25][N:26]=[N:27][C:17]=1[C:16]1[CH:19]=[CH:20][C:13]([C:4]2[CH:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2cc(Cl)c3cc(O)ccc3n2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Oc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3)cc(Cl)c2c1

Procedure:
Followed Scheme 4, route A. To a solution of 4-(4-chloro-6-hydroxyquinolin-2-yl)benzonitrile (65 mg, 0.23 mmol) in toluene (2 mL), was added TMSN3 (455 mg, 4.18 mmol) and Bu2SnO (15 mg, 0.069 mmol) at room temperature. The mixture was heated to reflux overnight. The volatiles were removed under reduced pressure. The residue was purified by prep-HPLC to afford Compound IV-11 (10 mg, 13.5%). 1H NMR (MeOD-d4, 500 MHz): δ 8.34 (d, J=8.5 Hz, 2H), 8.21 (s, 1H), 8.19 (s, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.47 (dd, J=2.5 Hz, J=9.5 Hz, 1H). MS (ESI): m/z 324.0 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:3]([OH:31])[CH2:4][C@@H:5]([NH:18][C:19](=[O:30])[C@H:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH:21][C:22]([O:24][CH3:25])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:39][O:40][C:41](=[O:42])[NH:43][C@@H:44]([C:48]([CH3:50])([CH3:49])[CH3:51])[C:45](=[O:46])[NH:1][C@@H:2]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:3]([OH:31])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[NH:18][C:19](=[O:30])[C@H:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH:21][C:22](=[O:23])[O:24][CH3:25]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution containing the product from Example 146C (0.035 g, 0.065 mmol) in tetrahydrofuran (0.70 mL) were added the product from Example 1F (0.012 g, 0.063 mmol), DEPBT (0.029 g, 0.097 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.321 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on a C18 column, eluting with a gradient starting with water (containing 0.1% trifluoroacetic acid) and ending with acetonitrile to give the product (0.021 g, 46% yield). 1H NMR (300 MHz, MeOH-d6), δ ppm 0.86 (s, 9 H), 0.88 (s, 9 H), 1.61-1.71 (m, 2 H), 2.58-2.65 (m, 1 H), 2.76-2.96 (m, 4 H), 3.57 (s, 3H), 3.65 (s, 3 H), 3.74-3.79 (m, 1 H), 3.81 (s, 1 H), 3.1 (s, 1 H), 4.19-4.28 (m, 1 H), 4.30-4.40 (m, 1 H), 7.10-7.28 (m, 7 H), 7.56 (d, J=3.3 Hz, 1 H), 7.78 (d, J=8.1 Hz, 2 H), 7.83 (d, J=3.3 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([CH3:27])=[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]4[CH:26]=[N:25][CH:24]=[N:23][C:19]=4[NH:20]3)=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[C:40](=[O:43])([O-])[O-:41].[K+].[K+]>CN(C)C=O.C1COCC1>[F:32][C:31]([F:34])([F:33])[C:40]([OH:41])=[O:43].[F:32][C:31]([F:34])([F:33])[C:40]([OH:41])=[O:43].[F:32][C:31]([F:34])([F:33])[C:40]([OH:41])=[O:43].[N:35]1([C:2]2[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[N:10][C:11]([CH3:27])=[C:12]([C:14]3[CH:22]=[C:21]4[C:17]([C:18]5[CH:26]=[N:25][CH:24]=[N:23][C:19]=5[NH:20]4)=[CH:16][CH:15]=3)[CH:13]=2)=[O:6])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: c1c[nH]cn1
Reactant: O=C([O-])[O-]
Reactant: Cc1ncc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)c2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Product: O=C(O)C(F)(F)F
Temperature: 120 °C

Procedure:
To a solution of 3-fluoro-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide (0.023 g, 0.049 mmol) in N,N-dimethylformamide (0.50 mL) was added 1H-imidazole (0.016 g, 0.24 mmol) and potassium carbonate (0.034 g, 0.25 mmol) and was heated at 120° C. for 16 hours. The reaction was diluted with THF, was filtered, was rotovaped and was purified by preparative LC to give the product. 1H NMR (400 MHZ, DMSO-D6): δ 13.06 (brs, 1H), 10.99 (s, 1H), 9.65 (s, 1H), 9.54 (brs, 1H), 9.13 (s, 1H), 8.99 (d, 1H), 8.64 (s, 1H), 8.44 (m, 3H), 8.36 (s, 1H), 8.25 (d, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.50 (m, 1H), 2.52 (s, 1H); MS (ES) (M+H)=514.