Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].FC(F)(F)C(C1S[C:40]([C:42]2[CH:43]=NC(C(F)(F)F)=CC=2)=NC=1C)O.BrC1C=C(CBr)C=CC=1C#N.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:43]1([C:2]2[CH:9]=[C:8]([CH2:10][O:11][CH:12]([C:17]3[S:21][C:20]([C:22]4[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=4)=[N:19][C:18]=3[CH3:32])[C:13]([F:14])([F:16])[F:15])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:42][CH2:40]1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(O)C(F)(F)F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(OCc1ccc(C#N)c(Br)c1)C(F)(F)F
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: N#Cc1ccc(CBr)cc1Br
Agent: OB(O)C1CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(OCc1ccc(C#N)c(C2CC2)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
309 mg 2-Bromo-4-{2,2,2-trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile (derived from 2,2,2-Trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethanol and 2-Bromo-4-bromomethyl-benzonitrile according to the method described in example 30), 32 mg tricyclohexylphosphine, 148 mg cyclopropylboronic acid and 470 mg K3PO4 mono hydrate were dissolved in a mixture of 4 ml toluene and 0.4 ml water. The reaction mixture was purged with argon, then 130 mg palladium (II) acetate were added. The reaction mixture was stirred at 100° C. for three hours. The cooled reaction mixture was diluted by addition of 100 ml ethyl acetate and filtered through a celite pad. The filtrate was washed twice with 25 ml water, then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 185 mg 2-Cyclopropyl-4-{2,2,2-trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)(=O)C.[Zn]>[NH2:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[F:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C(Nc1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)Nc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
Zinc dust (14 g) was added to a solution of 4-fluoro-3-nitro-N-phenyl-benzamide (1.99 g, 7.6 mmol) in acetic acid (80 mL) at 0° C. The mixture was stirred and allowed to warm to room temperature. After 4 hours, the mixture was filtered and the residue washed with ethyl acetate. The filtrate and washings were combined and taken to dryness by rotovap and the residue partitioned between ethyl acetate (200 mL) and saturated aqueous NaHCO3. The organic layer was washed with saturated brine, dried over MgSO4, filtered, and stripped of solvent. The residue was triturated in ethyl acetate/hexane and the suspended solid filtered off to afford the product (1.55 g); m.p. 167-170° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][Br:15])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][C:17]([CH2:21]O)([CH2:19][OH:20])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][Br:15])=[C:4]([C:9]2([CH3:10])[O:20][CH2:19][C:17]([CH3:21])([CH3:18])[CH2:16][O:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1OCCBr
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)COC(C)(c2cc(Cl)cc(Br)c2OCCBr)OC1
Yield: 63 %

Procedure:
A solution of 3′-bromo-2′-(2-bromoethoxy)-5′-chloroacetophenone (Reference compound No. 4-1, 4.4 g, 10 mmol), neopentylglycol (1.2 g, 1.2 mmol) and p-toluenesulfonic acid monohydrate (0.22 g, 12 mmol) in anhydrous toluene (50 mL) was refluxed overnight. After cooling, ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction mixture and the whole was partitioned. The organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the title reference compound (2.8 g) as a pale yellow oil (Yield 63%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][C:18]([NH:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:19]>C(#N)C.O>[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]([NH:20][C:21]2[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=2[CH:31]([CH3:33])[CH3:32])=[O:19])[CH2:12][CH2:11]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Potassium carbonate (1.52 g, 11 mmol) was added to a solution of 1-(2-hydroxyethyl)piperazine (1.43 g, 11 mmol) and 2-bromo-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide in acetonitrile (50 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried oven anhydrous sodium sulfate and the solvent was evaporated therefrom. The crude crystals were recrystallized from acetone-hexane to provide 2.5 g (yield 69%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide as colorless needles.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH2:40][C@H:41]([OH:48])[C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)C(=O)OC(C)(C)C)=[CH:26][CH:25]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH2:20][CH2:21][O:22][CH3:23])(=[O:19])=[O:18])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:49]>O1CCOCC1>[ClH:49].[ClH:49].[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][CH2:40][C@H:41]([OH:48])[C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH2:20][CH2:21][O:22][CH3:23])(=[O:18])=[O:19])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: COCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)cc1OC1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[[(2-methoxyethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (199 mg) in 1,4-dioxane (2.0 ml) was added hydrogen chloride in 1,4-dioxane (4N, 2.0 ml) at room temperature and the mixture was stirred at the same temperature 3 hours. The mixture was evaporated under reduced pressure to give 3-(cyclohexyloxy)-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-N-[(2-methoxyethyl)sulfonyl]-4-biphenylcarboxamide dihydrochloride (153 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2C[C@H]1CCCN1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (270 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring over 10 min. The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.216 g (crude) of 3-[4-(3-fluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]Cl.[C-:19]#[N:20].[Na+].CC(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(C)c(OCc2ccccc2CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Yield: 97.9 %

Procedure:
2-(2,5-Dimethylphenoxymethyl)benzyl chloride (Purity: 86.8%, 1.50 g, 5 mmol), 95% sodium cyanide (0.31 g, 6 mmol), triethylbenzylammonium chloride (0.06 g, 0.25 mmol), acetone (4 ml) and water (2 ml) were added. The mixture was heated under reflux for 5 hours. After completion of the reaction, water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 97.84).
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37]([O:39][CH2:40][C:41](=[O:45])[N:42]([CH3:44])[CH3:43])=[O:38])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[C:37]([O:39][CH2:40][C:41](=[O:45])[N:42]([CH3:43])[CH3:44])=[O:38])=[O:19])=[CH:21][CH:22]=1
Reactant: CN(C)C(=O)COC(=O)c1c(O)ccc2cc(C(=N)N)ccc12
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)COC(=O)c1c(OC(=O)c2ccc(NC3=NCCN3)cc2)ccc2cc(C(=N)N)ccc12
Reaction time: 2 h
Yield: 37.6 %

Procedure:
15 Milliliters of anhydrous pyridine was added to 1.0 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-benzoic acid.hydrochloride, 1.38 g of 6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol.hydrochloride, 1.28 g of DCC and 50.5 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. Then, the precipitate was collected by filtration, and dissolved by adding thereto 50 ml of warm DMF, 0.5 ml of 1N-hydrochloric acid and 2 ml of water, followed by stirring for 1 hour under cooling with ice. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of DMF, and the solution was added dropwise to a mixed liquid of 150 ml of acetone and 50 ml of ether, followed by stirring for 1 hour under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 5 ml of DMF and 0.7 ml of concentrated hydrochloric acid, and the solution was added dropwise to 150 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 447.8 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([N:18]=[C:19]=[S:20])[CH:17]=1)=[CH:5]2.[NH2:23][C@@H:24]([CH2:33][OH:34])[C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([NH:18][C:19]([NH:23][C@@H:24]([CH2:33][OH:34])[C@@H:25]([OH:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[S:20])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)N[C@@H](CO)[C@@H](O)c1ccccc1

Procedure:
The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (0.167 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant The resulting orange oil/foam was triturated with hexanes/ether to give the product as an orange solid (0.155 g), mp (slow decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10][C:11]3([O:21][CH2:20][CH2:19][O:14]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(Br)cc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a round bottom flask containing methyl 1-(4-bromophenyl)-4-oxocyclohexanecarboxylate (4.64 g, 14.91 mmol) was added toluene (33 ml), ethylene glycol (8.32 ml, 149 mmol) and p-toluenesulfonic acid (85 mg, 0.45 mmol) at room temperature. The mixture was heated to 80 C. for 2 hours. The content was then cooled to room temperature and quenched with a saturated solution of sodium bicarbonate. The organic portion was washed with saturated sodium bicarbonate and the aqueous portion extracted with MTBE twice. The combined organic portion was dried over sodium sulfate and concentrated to afford a crude oil. Column purification afforded the title compound as viscous oil (5.30 g, quantitative yield). LC/MS, ESI-MS(+): 357.1, RT: 1.38 (Condition E).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([N:34]3[CH2:50][CH2:49][C:37]4([CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)[CH2:36][CH2:35]3)[C:31]([C:51]#[N:52])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:51]([C:31]1[C:32]([N:34]2[CH2:35][CH2:36][C:37]3([CH2:41][NH:40][CH2:39][CH2:38]3)[CH2:49][CH2:50]2)=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:52]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 8-(2-(6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1-carboxamido)-5-cyanopyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (intermediate 37D, 70 mg, 0.095 mmol) in THF (0.5 ml) and H2O (0.5 ml) was added conc. HCl (0.1 ml, 1.2 mmol). The reaction mixture was stirred at room temperature for 4 h, then conc. HCl (0.1 ml, 1.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (4×) and EtOAc (4×). The combined organic phases were then dried over Na2SO4, filtered and evaporated. The crude material was triturated with EtOAc and dried under high vacuum to give the title compound as an off-white powder. (UPLC-MS 3) tR 0.64 min; ESI-MS 476.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=3)[C:7]([CH2:21][NH:22][CH2:23][CH2:24]CCCC(O)=O)=[CH:6][C:5]=2[CH:4]=1.N>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=3)[C:7]([CH2:21][NH:22][CH:23]([CH3:24])[CH2:14][CH2:5][CH2:4][CH2:3][OH:2])=[CH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CNCCCCCC(=O)O)cc3cc(OC)c(OC)cc3c2c1
Agent: N
Product: COc1ccc2c(CNC(C)CCCCO)cc3cc(OC)c(OC)cc3c2c1

Procedure:
General procedure f from 35 (92%); yellow oil; 1H NMR (400.13 MHz) δ 7.88 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J=2 Hz, 1H), 7.44 (s, 1H), 7.13 (dd, J=4 Hz, 2 Hz, 1H), 7.05 (s, 1H), 5.99 (s, 2H), 3.94 (s, 9H), 3.80 (s, 2H), 3.73 (t, J=6 Hz, 2H), 2.75 (m, 2H), 1.50 (m, 4H), 1.28 (m, 4H); MS (DCI/NH3) m/e: 398 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([C:14]([O:16]C)=O)[NH:7]2>C(N)CCC>[CH2:6]([NH:7][C:14]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[NH:7]1)=[O:16])[CH2:5][CH2:4][CH3:3]
Reactant: COC(=O)C1Cc2c(ccc(OC)c2OC)N1
Solvent: CCCCN
Product: CCCCNC(=O)C1Cc2c(ccc(OC)c2OC)N1

Procedure:
Methyl 4,5-dimethoxyindoline-2(R/S)-carboxylate (0.447 g, 1.89 mmol) was dissolved in butylamine (35 ml), under nitrogen, and the solution was then stirred at reflux for three hours. After cooling the mixture, the remaining butylamine was removed under vacuum. The crude product was recrystallized from diethyl ether to give an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[C:11]([CH3:22])[CH:10]=2)=O)C>S(=O)(=O)(O)O>[CH3:22][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:4](=[O:3])[C:6]=3[C:7](=[O:23])[NH:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccc(C)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Product: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Temperature: 95 °C

Procedure:
A mixture of 1,2-dihydro-4-phenyl-7-methyl-2-oxo-3-quinoline carboxylic acid ethyl ester (2.5 g, 8.1 mmol) and conc. sulfuric acid (20 ml) was stirred with heat at 95° C. for 10 hours. The reaction mixture was poured into ice water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and methanol in this sequence to give 1.5 g (yield 70.6 of the title compound.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)NCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
In a 500 ml flame-dried flask, N-phenethyl-acetamide (6.53 g, 40.0 mmol) was dissolved in methylene chloride (65 ml), and acetyl chloride (7.22 g, 92.0 mmol) was added in one portion. The resulting solution was cooled to about 0° C., and aluminum chloride (18.1 g, 136 mmol) was added in portions over about thirty minutes. The solution was stirred for about five minutes at about 0° C., and the ice bath was then removed and the mixture was heated to reflux for about thirty minutes. After cooling to room temperature, the reaction mixture was poured over ice water, stirred for about ten minutes, and then extracted with methylene chloride (2×100 ml). The combined organic extracts were then washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting white solid (7.52 g, 92% yield) was ascertained to be about 90% pure by NMR, and was employed directly without further purification. LRMS ([M+H]+)=206.2.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[OH:15][CH2:16]/[C:17](=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[OH:15][CH2:16][C@@H:17]([C@H:25]([S:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19]
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](CO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of n-butyl lithium in hexanes (0.6 mL, 1.4 mmol) is added slowly to a mixture of 4-methoxybenzenethiol (2 g, 14 mmol) in THF (10 mL) at 0° C. After 2 minutes a solution of t-butyl (E)-2-hydroxymethyl-7-phenylhept-2-enoate (2.2 g, 7.59 mmol) in THF (7 mL) is added and the reaction is allowed to warm to room temperature. After 1 hours the reaction is concentrated in vacuo and the crude product is purified by column chromatography using gradient elution (silica, 15 to 30% ether in petroleum ether) to give (±)-t-butyl (2R*,3R*)-2-hydroxymethyl-3-(4-methoxyphenylsulfanyl)-7-phenylheptanoate (3 g, 92%): 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.30-7.25 (m, 2H), 7.20-7.13 (m, 3H), 6.86-6.81 (m, 2H), 4.07-3.98 (m,1H), 3.93-3.86 (m, 1H), 3.80 (s, 3H), 3.26-3.19 (m, 1H), 2.67-2.60 (m, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.38 (t, J=6.6 Hz, 1H), 1.65-1.47 (m, 6H), 1.46 (s, 9H); MS (FAB) m/e 430 (M+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.O.[OH-].[Li+].[ClH:25]>C1COCC1.O>[ClH:25].[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]([OH:21])=[O:3])[CH3:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(F)cc1)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 72 %

Procedure:
To a solution of [(4-fluoro-phenyl)-methyl-amino]-phenyl-acetic acid ethyl ester (I70) (0.59 g, 2.05 mmol) in THF (10 mL) and water (10 mL), is added lithium hydroxide hydrate (0.26 g, 6.14 mmol). The reaction is stirred at RT for 3.5 hours and then at 70° C. for 24 hours. 3N HCl is added till pH is about 1 and the mixture is evaporated. Water (15 mL) is added and the residue is triturated obtaining a pale brown suspension that is filtered on a buckner funnel, washed with water and then with acetonitrile. The solid is dried under vacuum at 40° C. overnight to obtain intermediate I119 as a pale brown powder (0.44 g, 72% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)C1C=CC=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:49][CH3:50])[CH:45]=2)[CH:40]=1)(=O)=O>>[CH3:50][O:49][C:44]1[CH:45]=[C:46]2[C:41]([CH:40]=[C:39]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:48][CH2:47]2)=[CH:42][CH:43]=1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitrophenyl)tin (7.3 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide the title compound (1.5 g).