Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[CH3:3].S(Cl)([Cl:21])=O>>[ClH:21].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:1])=[O:11])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CCOc1ccccc1C(=O)O
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)Cl

Procedure:
Reaction of 2-(2-diethylaminoethoxy)benzoate hydrochoride with thionyl chloride as described in the procedure of Example 6 gives 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]([CH3:19])[C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)C1CCNCC1
Temperature: 27.5 °C
Reaction time: 6 h
Yield: 127.6 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) in DCM (400 mL) was added trifluoroacetic acid (150 mL) and the resulting mixture was stirred for 6 h at 25-30° C. After completion of the reaction, the solvent was removed under reduced pressure to afford 40 g of N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:35]=[CH2:36])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@@:16]3([OH:34])[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@H:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]3)=[CH:12][CH:11]=2)[CH:9]=1.[CH3:37]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:35]=[CH2:36])=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C@@:16]3([O:34][CH3:37])[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[O:22])[C@H:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]3)=[CH:14][CH:15]=2)[CH:9]=1
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)cc1-c1ccc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
NaH (60% in oil) (106 mg, 2.65 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (740 mg, 1.474 mmol) and methyl iodide (0.166 mL, 2.65 mmol) at 0° C. in DMF and stirred at this temperature and allowed to warm up to r.t. overnight. The reaction was then quenched with saturated NH4Cl solution and ether. The ether layer was washed with brine, dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (5-40% EtOAc in hexanes) to give semi purified product (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-1,2-dicarboxylate (333 mg, 0.645 mmol, 44% yield) as a clear oil. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 1.01-1.06 (m, 2H) 2.52 (dd, J=13.12, 8.85 Hz, 1H) 2.78-2.87 (m, 1H) 2.97 (d, J=5.19 Hz, 3H) 3.65 (s, 1H) 3.67-3.75 (m, 3H) 3.77 (d, J=8.85 Hz, 3H) 3.96-4.08 (m, 1H) 5.21 (d, J=10.99 Hz, 1H) 5.68 (d, J=17.40 Hz, 1H) 6.59 (ddd, J=17.47, 11.06, 2.29 Hz, 1H) 7.26 (d, J=2.14 Hz, 1H) 7.29-7.35 (m, 3H) 7.35-7.40 (m, 2H) 7.56 (d, J=8.24 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.CN[C@@H]1CCCC[C@H]1NC.[I-:35].[Na+]>C(O)CCC.C(OCC)(=O)C.[Cu]I>[I:35][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: [I-]
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1cc(I)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 5-Bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (300 mg, 0.713 mmol) in butanol (3 ml), (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (20 mg, 0.142 mmol), copper(I) iodide (13.6 mg, 0.07 mmol) and sodium iodide (214 mg, 1.43 mmol) were added. The resulting mixture was stirred at 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound as a yellow oil (274 mg, 85%). 1H NMR (300 MHz, CDCl3): δ 7.55-7.57 (m, 2H), 7.30-7.35 (m, 2H), 7.16-7.20 (m, 2H), 4.74 (s, 2H), 4.318 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[C:26]([CH3:30])=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:27]2[C:26]([CH3:30])=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Cc1nn(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(CCc2ccccc2C2(C(N)=O)CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (0.070 g, 0.63 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.032 mmol) in 1,4-dioxane (1.0 mL) was stirred in the microwave at 120° C. for 2 hours. Additional 1,4-dioxane (1.5 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for a further 4 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 15-100% EtOAc in petroleum benzine 40-60° C.). Fractions containing suspected product were combined and adsorbed onto silica and purified by column chromatography (Biotage Isolera, 12 g SiO2, 0-5% MeOH in DCM) to give the title compound 26 as a pale yellow solid (0.030 g, 25%). LCMS-D: rt 3.24 min; m/z 411 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12](C=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl.C(O)C.[OH-].[Na+]>O>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=CN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(C3CCNCC3)nsc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
Reflux a solution of 4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinecarboxaldehyde (Tetrahedron Lett., 1993, 34, 6525–6528, 12 g, 0.045 mol), 3N hydrochloric acid and ethanol (100 mL) for 3 hours. Stir at ambient temperature for 16 hours, add water and stir with ice bath chilling while adding sodium hydroxide solution until the mixture was basic. Extract with ethyl acetate, wash the extract with water, dry (MgSO4), filter and concentrate the filtrate to afford an oil which solidified on standing to afford 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (9.2 g). React 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole under conditions as described for Example 11 to afford the title compound (0.25 g, 61% yield), LC/MS (APCI) m/e 510 (MH+), retention time 4.38 min.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35][CH:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060 g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield: 0.035 g (57.37%). 1H NMR (400 MHz, CD3OD): δ 9.00 (d, J=1.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 7.98-7.90 (m and dd, 3H), 7.85 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.51-7.49 (two overlapping d, 2H), 7.35-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.84-1.81 (m, 2H), 1.52-1.49 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −76.94 (TFA), −112.22, −122.76 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@@H:24]1OC(=N)C(Cl)(Cl)Cl)(=[O:21])[CH3:20].C(=O)([O-])O.[Na+]>ClCCl>[C:19]([O:22][C@@H:23]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:24]1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: C=CCOc1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 2-(4-allyloxybenzyl)phenol (0.20 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose(0.45 g) in dichloromethane(8.5 mL) was added boron trifluoride-diethyl ether complex (0.12 g), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][O:18][C:19](=[O:23])[CH:20](Br)[CH3:21]>CO.CCN(C(C)C)C(C)C>[CH3:17][O:18][C:19](=[O:23])[CH:20]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:21]
Reactant: COC(=O)C(C)Br
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (0.9 g, 3.9 mmoles) in MeOH (13 mL) and DIPEA (1.5 mL) was treated with 2-bromo-propionic acid methyl ester (0.48 mL, 4.3 mmoles) and stirred overnight at 70° C. The MeOH was removed under reduced pressure and the residue was purified (silica gel, 10-40% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:35]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), phenylboronic acid (0.507 mmol, 2.7 eq), Pd(PPh3)4 (83.6 mg, 0.0723 mmol, 25 mol %), and K2CO3 (200.4 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.18 (d, J=6.8 Hz, 3H), 2.24-2.40 (m, 4H), 3.18-3.27 (m, 2H), 3.59 (dt, J=12.8, 3.3 Hz, 2H), 4.59 (dddd, J=10.0, 5.1, 4.9 Hz, 1H), 6.42 (q, J=6.7 Hz, 1H), 7.38-7.50 (m, 3H), 7.73-7.83 (m, 4H), 7.88 (d, J=9.9 Hz, 1H), 8.01 (s, 1H), 8.05 (s, 1H), 8.25 (d, J=9.9 Hz, 1H), 8.35 (br s, 2H). MS (ES+): m/z 522.20 (20) [MH+]. HPLC: tR=2.12 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6]C=CC=1.N(CC1CC1)=[N+]=[N-].[C:18]([C:20]1[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=1)#[CH:19]>>[CH:2]1([CH2:1][N:8]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=3)[N:10]=[N:9]2)[CH2:7][CH2:6]1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [N-]=[N+]=NCC1CC1
Product: CCOC(=O)c1sc(-c2cn(CC3CC3)nn2)nc1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with (azidomethyl)cyclopropane to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 70% yield: 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 4.39-4.19 (m, 4H), 2.69 (s, 3H), 1.38-1.19 (m, 4H), 0.74-0.64 (m, 2H), 0.48-0.37 (m, 2H); MS (ES+) m/z 293.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:10][C:11]1([CH3:20])[O:15][C@H:14]([CH2:16][CH:17]=O)[C:13](=[O:19])[O:12]1.C(O)(=O)C.[BH4-].[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:17][CH2:16][C@H:14]2[O:15][C:11]([CH3:20])([CH3:10])[O:12][C:13]2=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: Nc1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)OC(=O)[C@@H](CCNc2cc(F)cc(F)c2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31.0 mmol), (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (4.9 g, 31.0 mmol) and acetic acid (1.7 ml, 31.0 mmol) in 1,2-dichloroethane (100 mL) under nitrogen at 0° C. was added sodium borohydride (1.17 g, 31.0 mmol mol) in portions over 10 minutes. The resulting mixture was stirred at RT for 2.5 hours. After cooling to 0° C. the reaction mixture was quenched by the careful addition of saturated aqueous NaHCO3 (100 mL) followed by DCM (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to provide the crude (R)-5-[2-(3,5-difluorophenylamino)ethyl]-2,2-dimethyl-1,3-dioxolan-4-one as a yellow oil (8.07 g, 29.7 mmol, 96% yield) which was used without any further purification in the next reaction step. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=272.3; tR=1.76 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:8])=[O:5].CN1CC[CH2:28][C:27]1=[O:31].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:27](=[O:31])[CH3:28])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:5]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(NC(C)=O)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.10 g (0.3 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(5-amino-2-methoxyphenyl)urea was admixed with 1 ml of N-methylpyrrolidone, 0.11 g (0.3 mmol) of acetic anhydride and stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of H2O and extracted three times with 20 ml of ethyl acetate each time. The combined organic phase was washed with H2O, concentrated and dried. The crude product was purified by preparative HPLC (column: Waters Xterra™ MS C18, 5 μm, 30×100 mm, eluent: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 0.03 g of the desired product was obtained.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C@H:15]1[NH:27][C@H:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][N:27]1[C@H:15]([CH3:14])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[C@H:26]1[C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:33]=1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)/C=C/c1ccc([C@H]2N[C@H](C)Cc3c2[nH]c2ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (291 mg, 1.30 mmol) was added to a solution of (E)-methyl 3-(4-((1R,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (300 mg, 0.87 mmol) and N,N-diisopropylethylamine (0.226 ml, 1.30 mmol) in 1,4-dioxane (5 ml). The mixture was stirred at 90° C. for 1 hour then the mixture was evaporated to dryness and the residue was partitioned between DCM (30 nil) and water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the extracts combined with the organic layer. The combined extracts were filtered through a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 15% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (314 mg, 86%) as an off-white solid. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.87 (3H, d), 1.06 (3H, d), 1.9-2.28 (2H, m), 2.55-2.8 (3H, m), 2.97-3.21 (1H, m), 3.72 (3H, s), 4.31-4.69 (2H, m), 4.88 (1H, s), 6.60 (1H, dd), 6.98 (1H, t), 7.04 (1H, t), 7.17-7.35 (3H, m), 7.44 (1H, d), 7.55-7.76 (3H, m), 10.65 (1H, s). m/z: ES+ [M+H]+ 421.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
Ethyl cyanoacetate (3.475 mL, 1.3 equiv), ammonium acetate (1.16 g, 0.6 equiv), acetic acid (1.725 mL, 1.2 equiv) were added to a solution of N-Boc-4-piperidone (5 g, 25.11 mmol) in toluene (55 mL). The mixture was heated at 110° C. for 2 h, 85° C. overnight, then at 135° C. for 4 h. The mixture was washed with 5% aq NaOH (15 mL), water (15 mL) and brine (10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120-g silica gel cartridge, eluted with a 5 to 40% EtOAc in hexanes gradient, to afford tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (4.71 g, 64%) as an off-white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2.Br[CH2:27][C:28]([O:30]CC)=[O:29]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH:20]([CH2:27][C:28]([OH:30])=[O:29])[CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
n-Butyl lithium (3.27 g, 51.04 mmol) was added to a solution of di-isopropyl amine (6.88 g, 68.11 mmol) in THF (50 mL) at −60° C., and the mixture was stirred for 0.5 h. 6-methoxy-1-tetralone (6 g, 34.09 mmol) in THF (10 mL) was slowly added to the reaction mixture, the mixture was stirred for 45 min and ethyl bromoacetate (11.9 g, 71.25 mmol) was added. The reaction mixture was then stirred at room temperature for 16 h and quenched with saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (X2), combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentration to give 5.3 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:9][C:8](=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a mixture of phenylacetic acid (327 mg, 2.40 mmol, 1.2 equiv.) and 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (459 mg, 2.00 mmol) in CH2Cl2 (10 mL) were added DCC (495 mg, 2.40 mmol, 1.2 equiv.) and DMAP (12.2 mg, 100 μmol, 0.1 equiv.). The reaction mixture was allowed to stand overnight. After filtration, the liquid phase was washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by CC (SiO2, hexane/EtOAc 4:1). The ester (672 mg, 97%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 5H), 4.14 (t, 2H, J=6.8 Hz), 4.03 (d, 2H, J=13.2 Hz), 3.61 (s, 2H), 2.60 (dt, 2H, J=2.0, 12.8 Hz), 1.56 (m, 5H), 1.45 (s, 9H), 1.06 (m, 2H).