Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Cu][C:15]#[N:16].O.C(OCC)C>CN1CCCC1=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]#[N:16])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: N#C[Cu]
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(C=O)c(C(F)(F)F)c1
Temperature: 200 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
To a solution of 4-bromo-2-(trifluoromethyl)benzaldehyde (2.0 g) in N-methylpyrrolidin-2-one (39.5 mL) was added copper(I) cyanide (1.42 g). The reaction mixture was stirred at 200° C. for 3 hr, allowed to cool to room temperature, poured into water, and diethyl ether was added. The insoluble material was removed by filtration through celite. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.610 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[S:7]1[C:11]2[CH:12]=[C:13]([C:16](OCC)=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1>C1COCC1>[S:7]1[C:11]2[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CCOC(=O)c1ccc2ncsc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 76 mg of LiAlH4 in dry THF (20 mL) under N2 was added dropwise and at 0° C. a solution of ester 39 (207 mg, 1 mmol) in dry THF (6.7 ml). After 2 h. the ice bath was removed and the mixture was stirred overnight at room temperature, then cooled to 0° C. The excess of LiAlH4 was destroyed very cautiously by a saturated solution of NH4Cl. The organic layer was removed and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2CO3) and evaporated, obtaining an orange oil that was purified by column chromatography, eluting with EtOAc/MeOH (90/10). 1H NMR (CD3OD): δ 9.20 (s, 1H), 8.02 (m, 2H), 7.53 (d, 1H, J=8.04 Hz), 4.76 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Si:37]([C:41]#[CH:42])([CH3:40])([CH3:39])[CH3:38]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][Si:37]([C:41]#[C:42][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])([CH3:40])[CH3:39]
Reactant: NC(=O)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-iodobenzamide (I29) (1.65 g, 6.66 mmol), Cu(I)I (127 mg, 0.666 mmol) and triphenylphosphine (524 mg, 2.00 mmol) in THF (100 mL) and triethylamine (4.64 mL, 33.3 mmol) was sonicated for 10 minutes under a nitrogen atmosphere. PdCl2(PPh3)2 (642 mg, 0.67 mmol) and TMS acetylene (1.88 mL, 13.3 mmol) were then added and the reaction stirred at room temperature for 3 days. The volatiles were evaporated in vacuo and the residue chromatographed on silica gel (0-50% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I30) (1.53 g); 1H NMR (400 MHz, CDCl3) δ 7.78 (t, J=1.5 Hz, 1H), 7.67 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.53-7.48 (m, 1H), 7.29 (td, J=7.8, 0.5 Hz, 1H), 0.15 (s, 9H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.C(N(CC)CC)C.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:14])[N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:12]2
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: COCCN
Solvent: CCN(CC)CC
Product: COCCN1Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A mixture of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.0 g, 3.9 mmol), triethylamine (391 mg, 3.9 mmol) and 2-methoxy-ethylamine (348 mg, 4.6 mmol) was heated under reflux for 2 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, Heptane:EtOAc 1:1 to EtOAc) to afford the title product (260 mg, 30%) as a light yellow solid. MS m/e=221.3 (M+).
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Solvent: O
Solvent: CCO
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(cis-4-(1,1-Difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (32 mg, 0.083 mmol) was dissolved in EtOH (5 mL). Then LION (60 mg, 2.5 mmol, 30.0 eq.) in 1 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. LCMS showed starting material was gone. Solvent was removed. DCM was added and filtered. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give product (12 mg, 40%) as a slight yellow solid. EDI-MS (M-NH2): 347.0. HPLC: 98.82%. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.72-7.66 (m, 2H), 7.49 (d, 1H), 7.10 (d, 2H), 4.30-4.27 (m, 1H), 3.78-3.68 (AB, 2H), 3.18 (b, 3H), 2.32-2.30 (m, 2H), 2.04-1.99 (m, 2H), 1.63-1.19 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH3:12])[CH:5]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:13]
Reactant: COC(=O)c1ccc(I)c(OC)c1
Reactant: OB(O)c1ccc(F)cc1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2)c(OC)c1
Temperature: 100 °C
Yield: 92.2 %

Procedure:
4-Iodo-3-methoxy-benzoic acid methyl ester (292 mg, 1 mmol) and para-fluorophenylboronic acid (160 mg, 1.14 mmol) and Pd(PPh3)4 (80 mg, 0.069 mmol) and Cs2CO3 (600 mg, 1.84 mmol) is mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 4 hours. After which, the mixture is allowed to cool to room temperature and an aqueous work up is performed and the residue purified to afford the desired product (240 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=O)[CH3:10])=[C:4]([F:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](=[N:14]/[NH2:15])/[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: NN
Reactant: CC(=O)c1cc(F)c(Br)cc1F
Solvent: CCO
Solvent: O
Product: C/C(=N\N)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
1-(4-bromo-2,5-difluorophenyl)ethanone (500 mg, 1.042 mmol) was dissolved in ethanol (10 mL), then hydrazine hydrate (57.4 mg, 1.147 mmol) added and stirred at RT for 16 hr. A pale yellow solid was filtered off and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a brown-yellow solid (249 mg, 54% yield); 1H NMR (500 MHz, CHLOROFORM-d)delta 2.13 (3H, d, J=2.99 Hz), 7.28 (1H, dd, J=9.85, 5.60 Hz), 7.34 (1H, dd, J=9.14, 6.62 Hz).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=1)[NH:25][N:24]=[C:23]2[NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(Br)cc12
Yield: 32 %

Procedure:
20 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 2 g of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 μm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 75 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa; 50° C.) to give 2 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 50 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 500 mg of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a solid melting at 20° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2)=[O:5])[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([OH:14])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)N1C2CCC1CC(O)C2
Temperature: 70 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
To a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (3.0 g, 15.23 mmol) in methanol (20 mL) was added 5 mL Raney Nickel (50% aq slurry). The resultant mixture was degassed and charged with hydrogen (g) three times, heated to 70° C. and stirred for 12 hrs. The suspension was filtered through celite, and concentrated to provide a white solid (3.0 g, 100%). 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.0 Hz, 3H), 1.57 (m, 2H), 1.72 (app dd, J=1.4, 15.1 Hz, 2H), 1.94 (m, 2H), 2.12 (m 4H), 4.13 (q, J=7.1 Hz, 2H), 4.25 (m, 2H); MS (ESI+Q1MS) m/z 200 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3[N:17]=[C:18](SC)[N:19]=[CH:20][C:15]=3[C:14]([CH3:24])([CH3:23])[C:13]2=[O:25])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:9][C@H:10]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[C:14]([CH3:24])([CH3:23])[C:13]2=[O:25])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ncc2c(n1)N([C@H]1C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)C2(C)C
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cncnc32)C1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(trans-3-(5,5-dimethyl-2-(methylthio)-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate, INTERMEDIATE 63, (0.9 g, 2.378 mmol) in dry tetrahydrofuran (10 mL) was added cautiously palladium 10 wt. % on activated carbon (0.051 ml, 0.476 mmol) followed by triethylsilane (3.04 ml, 19.02 mmol). The mixture was stirred for 15 minutes under nitrogen atmosphere, filtered, and filtrate concentrated to give tert-butyl(trans-3-(5,5-dimethyl-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate. The crude tert-butyl(trans-3-(5,5-dimethyl-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate was redissolved in dioxane (10 mL) and treated with 4N HCl in dioxane (10 mL). After 30 minutes the reaction mixture was evaporated to dryness under reduced pressure to give the desired crude product 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride (0.55 g, 2.047 mmol, 86% yield). The product was used in next step without further purification. m/z: 233.0 (M+1-HCl).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][CH:8]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:7]1=[O:27])C.[Li+].[OH-]>C1COCC1.O>[C:17]1([C:15]([NH:14][CH:8]2[CH2:9][CH:10]=[C:11]([CH3:13])[CH2:12][N:6]([CH2:5][C:4]([OH:28])=[O:3])[C:7]2=[O:27])=[O:16])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CCOC(=O)CN1CC(C)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=CCC(NC(=O)c2nccc3ccccc23)C(=O)N(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {3-[(isoquinoline-1-carbonyl)amino]-6-methyl-2-oxo-2,3,4,7-tetrahydroazepin-1-yl}-acetic acid ethyl ester, 11, (70 mg, 0.28 mmol) in 3 mL of 3:1 THF/H2O is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified and extracted with EtOAc. The EtOAc layer is dried (Na2SO4) and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([NH:32]C(=O)OC(C)(C)C)[C@H:9]([OH:31])[CH2:10][CH:11]([O:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[S:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[N:18]2)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:32][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:31])[CH2:10][CH:11]([O:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[S:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[N:18]2)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A mixture of tert-butyl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinylsulfonyl)butyl]carbamate (563 mg, 1.01 mmol) and trifluoroacetic acid (5 mL) was stirred under an Argon atmosphere for 0.5 hrs. The acid was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with dichloromethane:methanol (98:2). Fractions containing the product were combined and evaporated in vacuo and dried under high vacuum to provide (3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinylsulfonyl)-3-pentanol as a foam (379 mg, 82%). H1-NMR (chloroform-D3): 1.66 (m, 11H), 2.51 (m, 1H), 2.86 (m, 1H), 3.07 (m, 1H), 3.23 (m, 1H), 3.32 (m, 1H), 3.84 (m, 1H), 4.90 (m, 1H), 7.20 (m, 5H), 8.16 (m, 1H), 8.28 (d, 1H), 8.70 (m, 1H), 8.99 (m, 2H). MS (ESI): 457 (M+H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=O.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[F:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH2:8][NH:4][CH2:3][CH2:1][OH:2]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCCNCc1ccc(F)cc1F
Temperature: 0 °C
Yield: 68 %

Procedure:
Ethanolamine (0.86 g, 14.07 mmol) was added to a solution of 2,4-difluorobenzaldehyde (2.0 g, 14.07 mmol) in methanol (50 mL) at RT. Sodium bicarbonate (7.0 g, 83.33 mmol) was added and the reaction mixture was stirred at reflux for 24 hours. The mixture was cooled to 0° C. and sodium borohydride (0.32 g, 8.42 mmol) was then added in lots, maintaining the temperature of the mixture at 0-5° C. The reaction mixture was allowed to warm to RT over a period of 4 hours. The reaction mixture was then diluted with DCM (50 mL), washed with brine (2×30 mL), dried (Na2SO4) and the solvents removed under reduced pressure to afford the title compound (1.79 g, 69%). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[CH3:24][N:25]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[N:26]1>>[OH:1][CH:2]1[CH2:23][N:22]([S:30]([C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)(=[O:32])=[O:31])[CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCNCC2O
Reactant: Cn1nccc1S(=O)(=O)Cl
Product: Cn1nccc1S(=O)(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)C(O)C1

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-(2,2,2-trifluoro-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 7 step B) and 2-methyl-2H-pyrazole-3-sulfonyl chloride. Light yellow solid. MS (ESI): 473.2 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:20])[CH3:19]>C(OCC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([O:20][CH2:18][CH3:19])=[NH:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N#CC1CCCN1C(=O)OCc1ccccc1
Solvent: CCOCC
Product: CCOC(=N)C1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Yield: 107.7 %

Procedure:
2-Cyano-pyrrolidine-1-carboxylic acid benzyl ester (17.0 g, 73.9 mmol) was dissolved in diethyl ether (100 mL). Ethanol (20.4 g, 444 mmol) was added and gaseous HCl was bubbled through the reaction mixture, while maintaining the temperature at −20° C. The temperature was maintained for 12 hours while stirring. The reaction mixture was concentrated under vacuo to afford 22.0 g (95%) of 2-ethoxycarbonimidoyl-pyrrolidine-1-carboxylic acid benzyl ester as a red oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:42]=[C:43]2[C:49]([O:50][CH2:51][CH3:52])=[N:48][N:47]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:44]2=[N:45][CH:46]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:40][C:41]2[CH:42]=[C:43]3[C:49]([O:50][CH2:51][CH3:52])=[N:48][N:47]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[C:44]3=[N:45][CH:46]=2)=[O:10])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOc1nn(C(=O)OC(C)(C)C)c2ncc(N)cc12
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OCC)nn3C(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
A mixture of 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.446 g, 1.51 mmol), EDCI (0.723 g, 3.77 mmol), and HOBt (0.578 g, 3.77 mmol) in DMF (6 mL) was stirred at room temperature for 25 minutes. tert-Butyl 5-amino-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.21 g, 0.755 mmol) was added to the reaction mixture, followed by the addition of Et3N (0.53 mL, 3.77 mmol). After stirring for 4 hours, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel flash column chromatography (10% MeOH in CH2Cl2) to afford tert-butyl 5-(6-chloro-2-fluoro-3-(propylsulfonamido)benzamido)-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (90 mg, 22% yield).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].Cl>O.CN(C=O)C>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[NH:17][C:18](=[O:26])[CH2:19]3)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cc2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
AlCl3 (20.0 g, 150 mmol) was placed in a dry 200 mL round bottom flask and DMF (3.30 mL) was added dropwise at 0° C. During the addition of DMF care was taken to ensure that the reaction was allowed to vent to the outside as this addition caused an exotherm to occur. Additionally as the DMF was added a white suspension formed. This suspension was allowed to stir for 30 min at room temperature, after which 4-nitrobenzoyl chloride (2.984 g, 16 mmol) was added. The mixture was warmed to 50° C. and stirred for 15 min at that temperature. The 50° C. mixture then was treated with oxindole (2.051 g, 15 mmol). The resulting reaction mixture was heated to 90° C. and allowed to stir for 5 hours during which the reaction mixture turned from a yellowish suspension to a thick black oil. The reaction was cooled to room temperature. Ice was added directly to the flask followed by water, turning the black oil into a pale yellow/white precipitate. Concentrated HCl(aq) (3 mL) was added to the reaction and the contents were stirred at room temperature for 15 min. The precipitate was collected via vacuum filtration. The crude solid was purified by washing with sat. NaHCO3(aq) providing 5-(4-Nitro-benzoyl)-1,3-dihydro-indol-2-one as a gray solid (4.05 g, 14.4 mmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([O:23]C)=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.Br>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1OC
Agent: Br
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-[(6-chloropyridin-3-yl)methyl]-1-methoxy-2-naphthoate (see Example 3, 0.200 g, 0.585 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide (1.0 M in dichloromethane, 1.76 mL, 1.76 mmol) dropwise. After 1 hour, the reaction was warmed to 0° C., treated with 6 mL of MeOH and warmed to room temperature overnight. To this reaction was added hydrobromic acid (33% in acetic acid, 2.50 mL, 15.2 mmol) dropwise, and the mixture was heated to 65° C. for 60 hours. Addition hydrobromic acid (33% in acetic acid, 1.50 mL, 9.14 mmol) was added, and the reaction was heated to 90° C. for 4 hours, cooled to room temperature, azeotroped 2× with toluene, and concentrated in vacuo to provide 4-[(6-chloropyridin-3-yl)methyl]-1-hydroxy-2-naphthoic acid that gave a mass ion (ES+) of 314.2 for [M+H]+.