Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(P(N(C)C)(N(C)C)=O)C.[CH3:17][C:18]1[N:23]=[C:22]([CH:24]2[S:29][CH2:28][CH2:27][CH2:26][S:25]2)[CH:21]=[CH:20][CH:19]=1.CI>CCCCCC.O1CCCC1.C(OCC)(=O)C.O.C(=S)=S>[CH3:17][C:18]1[N:23]=[C:22]([C:24]2([C:24]([S:25][CH3:26])=[S:29])[S:25][CH2:26][CH2:27][CH2:28][S:29]2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C2SCCCS2)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: S=C=S
Solvent: CCOC(C)=O
Product: CSC(=S)C1(c2cccc(C)n2)SCCCS1
Temperature: -71 °C
Reaction time: 0.67 h
Yield: 222.4 %

Procedure:
To a 1.6M solution (440 cc) of n-butyllithium in hexane, maintained under an atmosphere of argon and cooled to -71° C., a mixture (440 cc) of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47:53 by volume) is added dropwise in the course of 20 minutes. A solution of 2-(6-methyl-2-pyridyl)-1,3-dithiane (97 g) in a mixture (300 cc) of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47:53 by volume) is then added in the course of 30 minutes at a temperature in the region of -70° C. After 1 hour 40 minutes' stirring, carbon disulphide (53 g) dissolved in anhydrous tetrahydrofuran (220 cc) is added in the course of 40 minutes. After 45 minutes' stirring at -70° C., methyl iodide (97 g) dissolved in anhydrous tetrahydrofuran (220 cc) is added in the course of 30 minutes and at the same temperature. The reaction mixture is then stirred for 30 minutes at a temperature in the region of -65° C. and then for 50 minutes while the temperature is allowed to rise gradually to 10° C.; it is then poured into a mixture of distilled water (600 cc) and ethyl acetate (500 cc). After decantation, the aqueous phase is extracted twice with ethyl acetate (600 cc in total). The organic extracts are combined, washed twice with saturated aqueous sodium chloride solution (600 cc in total), anhydrous magnesium sulphate and decolorising charcoal are added, and the mixture is then kept for 15 hours at a temperature in the region of 5° C., filtered and then concentrated under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. To the product obtained (192.2 g) there is added some product (231.7 g) prepared under the same conditions in a previous operation, and the combined product is chromatographed on neutral silica gel (1.5 kg; 0.063-0.200 mm) contained in a column 8 cm in diameter. The product is eluted with methylene chloride, collecting one fraction (3.5 liters) followed by 7 fractions (600 cc). Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. The product obtained (276.5 g) is dissolved in boiling ethyl acetate (200 cc). The solution obtained is cooled and kept for 1 hour at a temperature in the region of 5° C. The crystals which appear are separated by filtration, washed twice with ethyl acetate (60 cc in total) and then 3 times with isopropyl ether (135 cc in total), and dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at 20° C. Methyl 2-(6-methyl-2-pyridyl)-1,3-dithiane-2-carbodithioate (153.9 g), m.p. 92° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][CH:8]2[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH2:33][CH2:34][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[C:12]([C:13]#[N:14])=[CH:11][CH:10]=3)[CH2:5][CH2:6][O:7]2)[CH2:17][CH2:18]1
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C#N)ccc2c1CCOC2CN1CCN(CCc2ccc3c(c2C)COC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile (0.04 mmol) in 5 mL of DCM was added (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (from Step B, Intermediate 17, 11 mg, 0.06 mmol) and NaBH(OAc)3 (34 mg, 0.16 mmol), the mixture was stirred at room temperature overnight. The reaction was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 1-({4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-5-(methyloxy)-3,4-dihydro-1H-isochromene-6-carbonitrile.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([C:55](O)=[O:56])=[CH:47]1>>[CH3:45][N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([C:55]([NH:27][CH:28]([C:30]2[N:35]=[N:34][C:33]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[N:32][CH:31]=2)[CH3:29])=[O:56])=[CH:47]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc1
Yield: 64.8 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 1-methyl-1h-indole-3-carboxylic acid (79 mg, 0.45 mmol) to give 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-3-carboxamide (107 mg) as a yellow solid. MS m/z 403 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][S:5]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:7])=[O:6]
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Step-3: To a stirred solution of 9.84 g (0.049 mol) of 2-trimethylsilanylethanesulfonyl chloride (SESCl) in DCM (100 mL) cooled to −78° C., was added the step-2 product, 4-(piperidin-4-yloxy)benzonitrile hydrochloride, (9.00 g, 0.038 mol). The mixture was stirred 30 min, warmed to −30° C., and stirred 3 h. To this mixture was added 20 mL of 1N NaOH solution added, and the DCM and aqueous layers partitioned. The aqueous layer was back extracted with DCM (50 mL) and the combined organic layers washed with brine (50 mL), saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was repeatedly crystallized from the minimum amount of DCM in hexanes to get the step-3 product, 4-[1-(2-trimethylsilanylethanesulfonyl)piperidin-4-yloxy]benzonitrile, compound B, as a white solid. (12.95 g, 94%): LCMS [MH+] 367, Rt 3.53; 1H NMR (300 MHz, (CD3)2CO-d6) δ 0.80 (s, 9H), 0.97-1.02 (m, 2H), 1.79-1.88 (m, 2H), 2.04-2.15 (m, 2H), 3.28-3.36 (m, 2H), 3.52-3.60 (m, 2H), 4.79 (septet, J=3.9 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)(Cl)(Cl)Cl>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 62 %

Procedure:
In 200 ml of carbon tetrachloride, 19.1 g (0.100 mol) of 4-cyano-2,3, 5,6-tetrafluorophenol and 11.3 g (0.125 mol) of acrylic acid chloride were dissolved. To the resultant solution, 20 g of molecular sieve 3 Å in diameter was added. The mixture was stirred under reflux for 38 hours. The resultant reaction mixture was cooled off and filtered to separate the molecular sieve. The filtrate was dried with magnesium sulfate and evaporated to dryness with a rotary evaporator. Consequently, there was obtained 15.2 g of 4-cyano-2,3,5,6-tetrafluorophenyl acrylate (yield 62.0% based on 4-cyano-2,3,5,6-tetrafluorophenol, purity 96.4%) having a melting point below determined.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2c(c1)CCN2
Yield: 83 %

Procedure:
5-Trifluoromethylindole (D42) was reduced in the usual way with sodium cyanoborohydride in glacial acetic acid to give the title compound (D43) (0.18 g, 83%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[C:17]([CH3:19])[N:18]=[C:4]2[N:3]=1.[NH4+].[Cl-].O.C1COCC1>C(O)C.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:5]2[N:16]=[C:17]([CH3:19])[N:18]=[C:4]2[N:3]=1
Reactant: Cc1nc2nc(Cl)c(-c3cccc(F)c3)c(Cl)n2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2nc(Cl)c(-c3cccc(F)c3)cn2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 7.9 %

Procedure:
10.4 g (35 mmol) 5,7-Dichloro-6-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine are given in 898 mL ethanol. 8.8 g (164.5 mmol) NH4Cl, 630 mL water, 340 mL THF and 14.6 g (224 mmol) zinc powder are added. The mixture is stirred at room temperature for 3.5 hours. The reaction mixture is filtered and the organic solvents are removed. The residue is diluted with water and extracted three times with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After evaporation of the solvent the residue is purified by chromatography giving 0.73 g (7.9%) of the desired product. Due to this low yield the zinc- and the Na2SO4 filter cakes are extracted with methanol delivering 2.3 g starting material.
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:36])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 111.1 %

Procedure:
A solution of (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (263 mg, 720 μmol) in dioxane (24.0 ml) was treated at room temperature with Lawesson's reagent (233 mg, 576 μmol). The reaction mixture was stirred at 80° C. for 4 hours. For the workup, the reaction mixture was poured on a saturated solution of sodium hydrogencarbonate then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and evaporated at reduced pressure to give brown oil. This residue was purified by chromatography on silica gel using a gradient of heptane/dichloromethane=100:0 to 20:80. The (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepane-3-thione (244 mg, 89% yield) was obtained as a white foam. MS (ISP): m/z=382.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>C(O)C>[OH:19][N:18]=[C:1]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NO
Reactant: CCOC(=O)c1ccc(C(=O)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=NO)C(C)C)cc1
Temperature: 36 °C

Procedure:
A mixture of ethyl 4-isobutyrylbenzoate (0.56 g, 2.54 mmol), hydroxylamine hydrochloride (1.06 g, 15.2 mmol), and sodium acetate (1.25 g, 15.2 mmol) in ethanol (36 mL) was heated to 36° C. for 2 h. The reaction was then concentrated and the residue was dissolved in EtOAc (200 mL). The organic phase was washed with water (2×20 mL), brine, dried (MgSO4), and concentrated to give crude ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate as a slight-yellow solid. LC-MS: (FA) ES+ 236.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([CH2:21][OH:22])[S:20][C:16]=2[CH:15]=1.C(Cl)Cl>O>[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([CH2:21][O:22][S:9]([CH3:8])(=[O:11])=[O:10])[S:20][C:16]=2[CH:15]=1
Reactant: OCc1nc2ccc(F)cc2s1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc2ccc(F)cc2s1
Reaction time: 1 h
Yield: 94 %

Procedure:
0.08 ml of triethylamine and 0.05 ml of methanesulfonyl chloride were added to a solution of 93.1 mg of 6-fluoro-2-hydroxymethylbenzothiazole [prepared as described in step (b) above] in 1.8 mi of methylene chloride cooled in an ice-water bath. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 125.3 mg (yield 94%) of the title compound as a solid having a melting point of 68° to 72° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:30])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:19]2)=O)(C)(C)C.O1CCCC1.[ClH:36].[SiH](CC)(CC)CC>O1CCOCC1>[ClH:36].[C:24]1([C:20]2[S:19][C:18]3=[N:17][C:16]([NH:15][C:14]([C@@H:9]4[CH2:10][O:11][CH2:12][CH2:13][NH:8]4)=[O:30])=[CH:23][N:22]3[CH:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1cn2cc(-c3ccccc3)sc2n1)[C@@H]1COCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 15 (0.06 mmol) was added to a mixture of tetrahydrofuran (0.7 mL) and 4M HCl in dioxane (0.7 mL). Et3SiH (0.408 mmol) was added and the reaction mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to give compound 16 as an orange solid in quantitative yield. MS (ESI, EI+) m/z=329.19 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]1[C:15]([C:16](Cl)=[O:17])=[C:14]([CH3:19])[N:13]=[C:8]12.[OH-].[NH4+:21]>>[C:16]([C:15]1[N:7]2[CH:6]=[CH:5][C:4]3[C:9]([C:8]2=[N:13][C:14]=1[CH3:19])=[CH:10][CH:11]=[CH:12][C:3]=3[Cl:2])(=[O:17])[NH2:21]
Reactant: [NH4+]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C(=O)Cl
Agent: Cl
Agent: [OH-]
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C(N)=O

Procedure:
To 28% ammonium hydroxide (50 ml) was added 7-chloro-3-chloroformyl-2-methylimidazo[2,1-a]isoquinoline hydrochloride (1.3 g) and the mixture was stirred under ice-cooling for 40 minutes. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of chloroform and methanol to give 3-carbamoyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (0.75 g).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)Br
Reactant: CCNCC
Product: CCOC(=O)C(C)N(CC)CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To ethyl 2-bromopropionate (0.15 moles), diethylamine (0.4 moles) was added, followed by stirring for 10 hours at room temperature. White solid was removed by filtration, and then the filtrate was distilled to obtain 2-diethylaminopropionic acid ethyl ester (0.120 moles).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([C:40]([CH3:42])=[CH2:41])[N:33]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1)#[N:2]>CO.[C].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:49])[F:48])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH:40]([CH3:42])[CH3:41])[N:33]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1)#[N:2]
Reactant: C=C(C)c1ccc(OC)c(-c2cc(OC)c(OC)cc2CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CN(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c(-c2nc(C(C)C)ccc2OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
4-(2-{(3-Cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropenyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (24.5 mg) is dissolved in methanol (2 ml), and thereto is added 10% palladium-carbon (10 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform:methanol=100:0→85:15) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(6-isopropyl-3-methoxy-pyridin-2-yl)-4,5-dimethoxy-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (21 mg). MS (m/z): 680 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:31])([CH:28]([F:30])[F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:31])([F:15])[CH:28]([F:30])[F:29])=[CH:20][CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(F)(F)C(F)F)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc(OCC(F)(F)C(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (137 mg, pale yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol) and 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (164 mg, 0.57 mmol, Amine-6, single enantiomer), and sodium bicarbonate (240 mg, 2.3 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:21](=[C:22]([C:24](=[O:26])[NH2:25])[CH:23]=2)[NH:20][C:19]2[CH:18]=[C:17]([N:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:16]=[CH:15][C:14]3=2)=[CH:7][C:6]=1[Cl:40].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:24]([C:22]1[CH:23]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:6]([Cl:40])[CH:7]=2)[CH:12]=[C:13]2[C:21]=1[NH:20][C:19]1[CH:18]=[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:16]=[CH:15][C:14]2=1)(=[O:26])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCBr)c(Cl)c4)cc23)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccc(OCCN5CCOCC5)c(Cl)c4)cc23)CC1
Temperature: 75 °C
Yield: 89.4 %

Procedure:
tert-Butyl 4-(6-(4-(2-bromoethoxy)-3-chlorophenyl)-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (342 mg, estimated purity 55%, ˜0.30 mmol, Example 409C) was dissolved in DMF (6 ml). Morpholine (0.5 ml, 5.7 mmol) and K2CO3 (160 mg, 1.16 mmol) were added and the mixture heated to 75° C. for 2 hour. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+25 ml saturated aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. Purification by prep HPLC gave 170 mg tert-butyl 4-(8-carbamoyl-6-(3-chloro-4-(2-morpholinoethoxy)phenyl)-9H-carbazol-2-yl)piperazine-1-carboxylate. MS (ESI) m/e+=634/636, m/e−=632/634 [1 Cl isotope pattern]. HPLC retention time 16.96 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.14 (s, 1H), 8.50 (d, 1H, J=1.3), 8.33 (b, 1H), 8.14 (d, 1H, J=1.5), 8.07 (d, 1H, J=8.8), 7.98 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.8, 2.3), 7.51 (b, 1H), 7.31 (d, 1H, J=8.8), 7.25 (d, 1H, J=2.0), 6.95 (dd, 1H, J=8.8, 2.0), 4.26 (t, 2H, J=5.8), 3.63-3.59 (m, 4H), 3.53 (b, 4H), 3.21-3.17 (m, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H), 1.46 (s, 9H).