Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.Cl.[CH3:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[NH:20][C@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH3:13]
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: C[C@@H]1CCCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCCC[C@@H]1Nc1c(F)cnc2[nH]ccc12
Temperature: 200 °C
Yield: 34.5 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (60 mg), (1S,2R)-2-methylcyclohexanamine hydrochloride (105 mg) and N,N-diisopropylethylamine (123 μL) in NMP (0.3 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification of the product by column chromatography (silica gel, gradient elution, 1:1 EtOAc/n-hexane to EtOAc) provided 5-fluoro-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (30 mg) as a tan solid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:29]([CH3:30])=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=3[CH3:31])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([CH3:31])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][C:29]=3[CH3:30])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCCC(CO)C3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCCC(CO)C2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-(6-(3-(hydroxymethyl)piperidin-1-yl)-3-methylpicolinamido)-3,5-dimethylbenzoate (0.06 g, 0.146 mmol) in THF:MeOH (4 ml:1 ml). After 12 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 3 with aqueous citric acid solution, and extracted with ethyl acetate (2×10 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and filtered to afford the title compound as an off-white solid (0.03 g, 48%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[C:18](=[O:24])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:26].S([O-])([O-])(=O)=O.[Mg+2]>O>[NH2:23][C:22]([C:21]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:24])=[CH:14][C:13]=1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: O=CO
Reactant: N#Cc1cc2c(cc1NC(=O)COCc1ccccc1)CCC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: NC(=O)c1cc2c(cc1NC(=O)COCc1ccccc1)CCC2=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A 22 L, 3 neck flask, equipped with an overhead stirrer, electric heating mantle, condenser, an N2 inlet, and a type-J Teflon® covered thermocouple, was charged with nitrile 10 (797 g, 2.49 moles—corrected for a purity of 75% by weight), formic acid (6400 ml) and magnesium sulfate (510 g). The resulting brown viscous mixture was heated to 40° C. with stirring and was allowed to stir at that temperature for 4 hours. At that time the reaction was judged to be complete by TLC and LC analysis. The reaction mixture was allowed to cool to 20° C. and stir at that temperature overnight. The following morning the reaction mixture was poured into 24 liters of water. The resulting yellow solid was collected by vacuum filtration rinsing with water (2×1500 ml) followed by isopropanol displacement wash (1×1500 ml). The crude product was allowed to air dry to a constant weight to afford 1030 g (886 g corrected for purity of 86% by weight-103%). The water content was 1.02% by Karl Fischer titration. The material was used directly in the next step without further purification. Rf=0.37 (65% EtOAc/hexanes) HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 nm, Phenomenex Jupiter C18 column 4.6 mm×250 mm at 29° C.: (st. material 11.6 min, amide 9.26 min, 87 A %) 1H NMR (DMSO, 300 MHz): 2.61-2.65 (m, 2H), 3.09-3.13 (m, 2H), 4.13 (s, 2H), 4.64 (s, 2H), 7.29-7.49 (m, 5H), 7.84 (br, 1H), 8.12 (s, 1H), 8.49 (br, 1H), 8.74 (s, 1H), 12.57 (br, 1H).
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[Cl:57][C:58]1[C:63]([NH2:64])=[CH:62][CH:61]=[C:60]([C:65]([F:68])([F:67])[F:66])[N:59]=1.CC([O-])(C)C.[Na+]>>[Cl:57][C:58]1[C:63]([NH:64][C:48]2[CH:49]=[C:50]3[C:45](=[C:46]([C:52]#[N:53])[CH:47]=2)[N:44]([CH3:54])[C@H:43]2[CH2:55][CH2:56][NH:40][CH2:41][C@@H:42]32)=[CH:62][CH:61]=[C:60]([C:65]([F:66])([F:67])[F:68])[N:59]=1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3ccc(C(F)(F)F)nc3Cl)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (40 mg, 20%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 2-chloro-6-trifluoromethyl-pyridin-3-ylamine(186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 408 (base, M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]#[N:10].[NH2:12][NH2:13]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH2:10])[NH:13][N:12]=1
Reactant: N#CCC(=O)c1ccccn1
Reactant: NN
Solvent: CCO
Product: Nc1cc(-c2ccccn2)n[nH]1
Yield: 30.2 %

Procedure:
3-(2-Pyridyl)-3-oxopropanenitrile (3.0 g, 0.37 mol) was dissolved in ethanol (22 mL) and treated with hydrazine (1.9 mL, 0.062 mol) at reflux for 24 hours. The reaction mixture was concentrated, diluted with brine and extracted into ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel chromatography eluting with 2-20% methanol in methylene chloride to afford 3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.0 g, 91% yield).
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 130 °C
Yield: 28.5 %

Procedure:
A stirred mixture of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.20 g, 0.55 mmol), (1R,2R)-2-aminocyclohexanol (0.19 g, 1.6 mmol), DIEA (0.71 g, 5.5 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (65 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.69-7.78 (m, 3H), 7.30 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 5.44 (s, 2H), 4.74 (d, J=4.8 Hz, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.00 (m, 1H), 1.87 (m, 1H), 1.58-1.60 (m, 2H), 1.15-1.25 (m, 4H); LCMS (ESI) m/z 415 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:46]I>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[I:46][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCCI
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a suspension of 0.5 g of tert-butyl N-(12-hydroxydodecyl)carbamate in 15 ml of toluene were added 0.28 g of imidazole, 1.09 g of triphenylphosphine and 0.84 g of iodine and the mixture was stirred for 0.5 hour. Then, 5 ml of tetrahydrofuran was further added and the mixture was stirred for 2 hours. To the reaction solution was added ethyl acetate and the mixture was washed successively with a 10% aqueous solution of sodium thiosulfate and water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 0.42 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH:12]([CH3:14])[CH3:13])[N:10]=[CH:11][C:3]=12.ClC1N=C(I)N=C2C=1N=CN2C(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH:12]([CH3:14])[CH3:13])[N:10]=[CH:11][C:3]2=[C:2]([NH:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1ncc2c(Cl)nc(Cl)nc21
Agent: CC(C)n1cnc2c(Cl)nc(I)nc21
Product: CC(C)n1ncc2c(NCCc3ccc(O)cc3)nc(Cl)nc21

Procedure:
Following the procedure of Example 128b, 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (U.S. Pat. No. 3,399,196) (a) (0.184 g, 0.795 mmol) was reacted with tyramine. The crude residue was purified by silica gel chromatography (25 to 75% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 332.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.[CH:33]1([CH2:36]O)[CH2:35][CH2:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:31]=[C:30]([O:32][CH2:36][CH:33]2[CH2:35][CH2:34]2)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: OCC1CC1
Reactant: CC(c1cc(-c2cnc(Oc3ccc(O)cc3Cl)s2)no1)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc(-c2cnc(Oc3ccc(OCC4CC4)cc3Cl)s2)no1)N1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of Example 30F (550 mg, 1.18 mmol), cyclopropylmethanol (0.14 mL, 1.76 mmol) and triphenylphosphine (462 mg, 1.76 mmol) in tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (0.28 mL, 1.76 mmol) at ambient temperature. The reaction was stirred for 16 hours, concentrated and purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 30% ethyl acetate in hexanes to provide 480 mg of the title compound as a white solid (78%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.28-0.39 (m, 2H) 0.53-0.65 (m, 2H) 1.12-1.30 (m, 1H) 1.82 (d, J=7.35 Hz, 3H) 3.88 (d, J=6.99 Hz, 2H) 5.56-5.69 (m, J=7.11, 7.11, 7.11 Hz, 1H) 7.03 (dd, J=8.82, 2.94 Hz, 1H) 7.17 (s, 1H) 7.23 (d, J=2.94 Hz, 1H) 7.53 (d, J=8.82 Hz, 1H) 7.83-7.97 (m, 5H); MS (ESI) m/z 522.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(O)=O.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:3])[C:4]#[CH:5]
Reactant: C#CC(C)(C)O
Reactant: Oc1ccc2ncccc2c1
Agent: Cl[Cu]
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and anhydrous trifluoroacetic acid (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with sodium hydrogencarbonate aqueous solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>CO>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: ClCCCCCBr
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCCCCl)C(C)=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of methyl acetoacetate [VI-2] (127.7 g, 1.1 mol) and methanol (200 g) is heated to 30° C. Thereto is added dropwise 28.1 % solution of sodium methoxide in methanol (192 g, 1.0 mol), and the mixture is stirred for 1 hour. Thereto is added 1-bromo-5-chloropentane [V-1] (155.5 g, 0.838 mol), and the mixture is reacted at 70° C. for 2 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and thereto is added toluene (500 g). The precipitated salt is removed by filtration. The toluene layer is washed with water and concentrated under reduced pressure to give methyl 7-chloro-2-(1-oxoethyl)heptanoate [II-2] (189.9 g, content; 88.7 %, yield; 91.2 %).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:14]([C:17]([C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:21]=2)([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:11]1([S:14]([C:17]([C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:35][CH:34]=3)[N:21]=2)([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH2:13][CH2:12]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.1 %

Procedure:
Phenyl chloroformate (0.215 mL, 1.71 mmol) was added dropwise to 4-[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (712 mg, 1.71 mmol) and sodium bicarbonate (215 mg, 2.56 mmol) in dioxane (15 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material (983 mg).
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[CH:28][C:29]#[N:30]>C(O)(=O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)#[N:30]
Reactant: N#CC=C(N)c1ccc(Cl)cc1
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(c2ccc(Cl)cc2)N1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 129 mg (0.724 mmol) 3-amino-3-(4-chlorophenyl)prop-2-enenitrile (Example 6A) in acetic acid (2 ml) was stirred for 30 min at 110° C. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 197 mg (64% of th.) of the racemic title compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:32]=[CH:31][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>O1CCOCC1.C(=O)(O)[O-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:21]1[CH:31]=[CH:32][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:34][C:20]=1[C:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cc(F)c1=O
Yield: 39.7 %

Procedure:
The title compound of Example 119, step 2 (40 mg, 0.16 mmol), 1-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene (58 mg, 0.16 mmol) and Pd(dppf)Cl2 (12 mg, 10%) in 1,4-dioxane (880 μL) and saturated bicarbonate solution (aq) (220 μL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (26 mg, 46%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (s, 3H) 3.60 (s, 3H) 6.91-6.99 (m, 1H) 7.16-7.30 (m, 1H) 7.49-7.62 (m, 2H) 7.76-7.86 (m, 2H) 8.00 (m, 2H) LCMS (M+H)+=410.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][C@@H:14]([NH:16][C:17]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:23])[CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 4-hydroxyphenyl acetate (60.8 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (70 g) and triphenylphosphine (105 g) in THF (300 mL) was added dropwise a solution (1.9 M, 210 mL) of diisopropyl azodicarboxylate in toluene at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in diethyl ether, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate), and then by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (70.9 g).
Reaction SMILES: C(C1C2CCSC=2C=CC=1)C=C.[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]2[CH2:20][CH2:21][S:22][C:18]=2[CH:17]=1)[CH:14]=[CH2:15].[OH:25]C1C=CC2SCCC=2C=1>>[CH2:13]([C:16]1[C:24]([OH:25])=[CH:23][C:19]2[CH2:20][CH2:21][S:22][C:18]=2[CH:17]=1)[CH:14]=[CH2:15]
Reactant: Oc1ccc2c(c1)CCS2
Reactant: C=CCc1ccc2c(c1)SCC2
Agent: C=CCc1cccc2c1CCS2
Product: C=CCc1cc2c(cc1O)CCS2

Procedure:
To a solution of BCl3 in methylene chloride (5.5 mL, 1.0M, 5.5 mmole) under N2 at -25° C. was added dropwise a solution of 5-allyloxy-2,3-dihydrobenzothiophene (1.0 g, 5.2 mmole) in methylene chloride (10 mL) keeping the temperature between -25° and -15° C. (10 minutes). The reaction mixture was stirred at -15° C. for 15 minutes. The cooling bath was then removed and the reaction mixture allowed to stir for another 1.5 hours. The reaction mixture was then poured into ice water (70 mL). An additional portion of methylene chloride (10 mL) was added and the layers separated. The aqueous layer was extracted an additional 2×20 mL methylene chloride and the combined organic layers were washed with NaHCO3 (sodium bicarbonate) (1×20 mL), H2O (1×20 mL) and brine (1×20 mL). After drying over Na2SO4, filtration and concentration afforded 0.56 g crude product. Purification by flash chromatography (90/10 hexane/EtOAc to elute) afforded, in order of elution: 64 mg (6.4%) 4-allyl-2,3-dihydrobenzothiophene (oil) 204 mg (20.4% 6-allyl-2,3-dihydrobenzothiophene (oil) and 146 mg (18.4%) 5-hydroxy-2,3-dihydrobenzothiophene.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([CH2:13][CH:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH2:15]2)[CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 2.02 mmol) was dissolved in THF (10 mL) at rt and 1 M LiOH sol. (2.02 mL) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 5 by addition of 1 M HCl sol. and solvents were removed in vacuo, to give 1-[6-(tert-butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid, which was used crude in the subsequent reaction.