Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:22]([O:24]CC)=[O:23])[C:13]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4]>C(O)C>[CH2:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:22]([OH:24])=[O:23])[C:13]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1N(C)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1ncc2c(N(C)C3CCOCC3)c(C(=O)O)cnc21
Temperature: 50 °C

Procedure:
Sodium hydroxide (0.43 g, 10.8 mmol) was added to a solution of Intermediate 51 in ethanol (10 ml, 95%). The reaction mixture was heated at 50° C. for 18 hours. The solvent was evaporated in vacuo and the residue dissolved in water and acidified to pH 3 by the addition of aqueous hydrochloric acid. The solution was extracted with DCM. The organic phase was separated using a hydrophobic frit (Whatman PTFE Folter Media with Polypropylene Housing 5 μM pore size) and the solvent evaporated in vacuo to give Intermediate 52 as a white solid (0.65 g). LCMS showed MH+=305; TRET=1.97 min.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of tert-Butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (852 mg, 2.60 mmol), vinylboronic acid pinacol ester (400 mg, 2.60 mmol), saturated aqueous sodium carbonate solution (12 ml), and tetrakis(triphenylphosphine)palladium(0) (84.8 mg, 0.0734 mmol) in dimethoxyethane (15 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (250 mg, 34.9%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:71][O:72][NH3+:73].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:73][O:72][CH3:71])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) prepared in Example 1f, EDCl (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (11 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:31])[CH2:9][CH2:8][N:7]([C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C)C=O>[F:31][C:4]1([F:3])[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:29])[CH3:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 24 mg, 1.1 eq.) was added to a mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 200 mg, 1.0 eq.) in N,N-dimethylformamide (2 mL) and stirred at 70° C. for 30 min. 4-Fluorobenzenesulfonyl chloride (115 mg, 1.2 eq.) was added and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with dichloromethane/methanol 49:1 to yield 167 mg (60%) of the desired product as yellow foam. MS (m/e): 564.4 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)([OH:22])=[O:21]>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:26]2[S:27][C:23]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[Cl:19]
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Reactant: O=C(O)c1ccc(B(O)O)s1
Product: Nc1ncc(-c2ccc(C(=O)O)s2)cc1OCc1c(F)ccc(F)c1Cl

Procedure:
5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylic acid was prepared following procedure 3 starting from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 5-carboxythiophene-2-boronic acid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl[C:21]1[N:25]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[N:24]=[CH:23][C:22]=1[C:36](=[O:44])[NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C=O)C.C(OCC)(=O)C>[CH:38]1([NH:37][C:36]([C:22]2[CH:23]=[N:24][N:25]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[C:21]=2[S:4][CH2:1][CH2:2][CH3:3])=[O:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCCS
Reactant: COC(=O)c1cccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1cccc(C(=O)OC)c1
Reaction time: 2 h

Procedure:
Propane thiol (48 mg, 0.57 mmol) was dissolved in DMF (3 mL) and treated at ambient temperature with a 1M solution of NaHMDS in THF (0.63 mL, 0.63 mmol). After stirring for 15 min a solution of methyl 3-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #19) (205 mg, 0.57 mmol) in DMF (5 mL) was added and stirring continued for 2 h. Ethyl acetate (50 mL) was added and the mixture washed with water (3×20 mL), dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica gel eluting with an EtOAc/DCM gradient (0-25%) to provide the title compound as a clear colourless oil. (175 mg, 75%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2c(C)csc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1csc2c(Cl)c(Cl)c(O)cc12
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 5.6 g of 6,7-dichloro-5-methoxy-3-methylbenzo[b]thiophene and 50 g of pyridine hydrochloride is stirred at 190°-195° for 2 hours. The cooled reaction mixture is diluted with water and extracted with three 300 ml-portions of ether. The combined ether extracts are washed, dried and concentrated to give a tan-colored solid, mp 137°-139°. Recrystallization from hexane gives 3.8 g of 6,7-dichloro-5-hydroxy-3-methylbenzo[b]thiophene as silky needles.
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[N:26][CH:27]=1.CC(C)([O-])C.[Na+].O>CS(C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:3]2[C:2]([O:35][C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:25]4[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=4)=[CH:34][CH:33]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccc(Oc3nccnc3C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (9.55 mL, 3.73 mmol), 4-(5-methylpyridin-2-ylamino)phenol (0.747 g, 3.73 mmol), and sodium tert-butoxide (1.07 g, 11.20 mmol) in DMSO (15 mL) was stirred at RT in 24 h. Water was added, and the reaction mixture was extracted with ether (3×), dried over MgSO4, concentrated and purified by ISCO (0-60% EtOAc/Hexanes) to give the light brown oil. MS (ESI, pos. ion) m/z: 462.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=C[S:10][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:8][C:7]1[C:6]([SH:10])=[C:5]([OH:11])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c2ncsc12
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1c(F)ccc(O)c1S
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-1,3-benzothiazol-7-ol (C14) (2.02 g, 11.93 mmol) in ethanol (20 mL) was treated with hydrazine monohydrate (12.7 mL, 167 mmol) and stirred for at 80° C. for 1 hour. The reaction was concentrated in vacuo and used directly in the following step.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:21])[CH2:3][CH2:2]1.OS(O)(=O)=O.[N+:27]([O-])([O-:29])=[O:28].[K+]>>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:27]([O-:29])=[O:28])=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:21])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1c2ccc(F)cc2CCN1c1cnccc1C1CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C1CC1
Yield: 49.2 %

Procedure:
2-(4-Cyclopropylpyridin-3-yl)-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (81A: 700 mg, 2.482 mmol) was reacted with conc. H2SO4 (5 mL) and KNO3 (276 mg, 2.73 mmol) for 4 hours to afford 400 mg of the product (49.14% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH:28]1(NC(C)C)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]([CH3:28])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Reactant: CC(C)NC1CCCCC1
Solvent: CI
Product: CCCCC(C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 7(c), a reaction was carried out using ethyl 2-(4-benzyloxybenzyl)caproate (2.04 g) and methyl iodide (1.12 ml) instead of 4-benzyloxybenzyl chloride and cyclohexylisopropylamine (1.48 ml) instead of diisopropylamine and the reaction mixture was treated to afford the desired compound (1.80 g) as a syrup.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])CCC.Br[C:27]1[S:28][C:29]2[S:35][CH2:34][CH2:33][C:32](=[O:36])[C:30]=2[N:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[C:27]1[S:28][C:29]2[S:35][CH2:34][CH2:33][C:32](=[O:36])[C:30]=2[N:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccnc2)nc1C
Reactant: O=C1CCSc2sc(Br)nc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: Cc1nc(-c2cccnc2)sc1-c1nc2c(s1)SCCC2=O
Temperature: 100 °C
Yield: 20 %

Procedure:
Tri-n-butyl-[4-methyl-2-(3-pyridyl)thiazol-5-yl]stannane (560 mg, 1.2 mmol, prepared as described previously) and 2-bromo-5,6-dihydrothiopyrano[3,2-d]thiazol-7-one (300 mg, 1.20 mmol), Tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.06 mmol) and Tri(2-furyl)phosphine (54 mg, 0.23 mmol) were dissolved in 10 ml of dioxane and placed in a steel tube. The mixture were evacuated, flushed with N2 3 times and heated at 100° C. for 18 hours. After cooling to ambient temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified with chromatography (Ethyl acetate: Petroleum ether=2/1) to give the title compound (83 mg, 20% yield). 1H NMR (400 Mz, CDCl3): δ2.79 (s, 3H), 3.04 (t, 2H), 3.46 (t, 2H), 7.43-7.45 (m, 1H), 8.43 (d, 1H), 8.69 (d, 1H), 9.20 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>C(O)C>[CH:39]1([NH:42][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:25]2[CH:34]=[CH:33][C:32]3[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=3[CH:26]=2)[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 75.8 %

Procedure:
In a manner similar to that of Example 1b, by reaction of 600 mg (1 mmol) of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 720 μl (11.5 mmol) of cyclopropylamine in 50 ml of ethanol. 420 mg of ethyl 4′-(5-cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white paste (yield=73%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[O:17][C:16](=[O:18])[C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[N:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1oc(N2CCC3(CC2)OCCO3)nc2ccccc12
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a stirring solution of 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoic acid (1.91 g, 6.25 mmol) in DMF (12 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g, 6.25 mmol). After 30 min, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed consecutively with 1 M citric acid, brine, satd aq sodium bicarbonate, and brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 1.36 g of the title compound; which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C(Cl)Cl.N1C=CC=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:8][S:11]([CH3:10])(=[O:13])=[O:12])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(Br)ccc1F
Reaction time: 4 h
Yield: 38.9 %

Procedure:
Dissolve 5-bromo-2-fluoro-phenylamine (1.40 g, 7.37 mmol), N,N-dimethylamino-4-pyridine (90 mg, 0.737 mmol), and methanesulfonyl chloride (1.69 g, 14.74 mmol) in CH2Cl2 (10 mL) and pyridine (10 mL). Stir under N2 for 4 h and concentrate in-vacuo. Dilute residue with 1.00N aqueous HCl (20 mL) and extract into ethyl acetate. Dry (MgSO4) and concentrate organics to a yellow solid. Dissolve in THF (20 mL) and add 1.0M tetrabutylammonium fluoride/THF (4.83 mL, 4.83 mmol). Heat to reflux for 3 h, then add H2O and brine. Extract into ethyl acetate, then dry (MgSO4) and concentrate organics to a white solid. Recrystallization from boiling toluene/hexanes affords 768 mg (39%) of the title compound as a white solid. MS (ES) 267 (M−H); HPLC shows 100% purity.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([C:9](=[O:34])[CH2:10][CH2:11][CH2:12][N:13]2[C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:20]3[C:15]([N:16]([CH3:33])[C:17](=[O:32])[N:18]([CH3:31])[C:19]3=[O:30])=[CH:14]2)[S:7][CH:8]=1>C(O)C>[Cl:3][C:4]1[N:5]=[C:6]([CH:9]([OH:34])[CH2:10][CH2:11][CH2:12][N:13]2[C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:20]3[C:15]([N:16]([CH3:33])[C:17](=[O:32])[N:18]([CH3:31])[C:19]3=[O:30])=[CH:14]2)[S:7][CH:8]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium borohydride (0.606 g, 16.03 mmol) was added portionwise to a suspension of 3-(6-(4-(4-chlorothiazol-2-yl)-4-oxobutyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (2.5 g, 5.34 mmol) in ethanol (53.4 mL) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C., the quenched with water (25 mL) and extracted with DCM (3×50 mL). The combined organic fractions were dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: c1ccc2c(c1)CNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2Cc3ccccc3C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), Isoindoline (23 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 16.3 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(isoindolin-2-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:16]#[N:17])[C:11](OCC)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(N(CC)CC)C>[NH2:17][C:16]1[N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=[C:11]([OH:12])[C:10]=1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: CCOC(=O)C(C#N)c1ccc2c(c1)OCO2
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Yield: 40.7 %

Procedure:
To a stirred suspension of ethyl 2-(1,3-benzodioxol-5-yl)-2-cyanoacetate (76 g) and benzylhydrazine hydrochloride (99 g) in ethanol (1300 ml), triethylamine (152 ml) was slowly added at room temperature. The solution was refluxed for two days, then concentrated under reduced pressure. To the dark residue, ethyl acetate (800 ml) and water (1000 ml) were added. The white precipitate was collected by filtration washed with water and ethyl acetate, then dried under educed pressure to give the title compound as a white solid (41 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([CH3:17])=[C:15]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[C:14]([CH3:27])=[N:13]1)C1C=CC=CC=1.C(OP(CC1C=CC(NC2N=C(NC3C=CC(C4C=C(C(OC)=O)N(CCCO)C=4)=NC=3C(=O)NC)C(C(F)(F)F)=CN=2)=C(OC)C=1)(O)=O)C>>[CH3:27][C:14]1[C:15]([B:18]2[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]2)=[C:16]([CH3:17])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[N:13]=1
Reactant: Cc1nn(CCCOCc2ccccc2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cc(C(=O)OC)n(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1
Product: Cc1nn(CCCO)c(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 100.2 %

Procedure:
1-[3-(Benzyloxy)propyl]-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 43C, 560 mg, 1.5 mmol) was hydrogenated using the procedure from Compound 38A to afford 421 mg of the desired title compound (99%). 1H NMR (400 MHz, CD3OD) δ 4.08 (t, J=7.1 Hz, 2H), 3.50 (t, J=6.1 Hz, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 1.95 (t, J=6.7 Hz, 2H), 1.30 (s, 12H). MS (ESI): m/z=280.37 [M+H]+. UPLC: tR=1.29 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18].COC(=O)C(OC)C(C1C=CC=C(OCC2C=CC=CC=2)C=1)O>>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[OH:13])[CH3:25]
Reactant: CCOCC(=O)OCC
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C(OCC)C(O)c1cccc(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 3-benzyloxy-benzaldehyde and ethyl ethoxyacetate via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (Example 291, Step 1) to afford the title compound as a colorless oil.