Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].Cl[C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]2=[O:29].CN(C=O)C>CCOCC.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>[OH:11][CH2:8][C:9]#[C:10][C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]2=[O:29]
Reactant: CCOC(=O)c1cn(C)c2ccc(Cl)nc2c1=O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(C#CCO)nc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Triethylamine (10 mL) is added to dry cuprous iodide (52 mg) under nitrogen. The mixture is stirred for 5 minutes and propargyl alcohol (50 μL) is added. After stirring another 5 minutes, dichlorobis(triphenylphosphine)palladium(II) (48 mg) is added. The mixture is again stirred for 5 minutes before the addition of ethyl 6-chloro-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxylate (Preparation 59, 367 mg) and DMF (10 mL). After stirring another 5 minutes, the remaining propargyl alcohol (660 μL) is added, and the reaction is tightly capped and stirred at 70° C. for 11 hours. After cooling, the dark mixture is diluted with ether (75 mL), sonicated to break up the solids, and filtered. The collected solid is washed with ether and dried under vacuum. The crude solid is recrystallized from 95% ethanol (100 mL, dissolved at reflux with the addition of a few drops of water, then cooled to 0° C. overnight), affording 219 mg (55%) of the title compound as a beige solid. Physical characteristics. 1H NMR (DMSO-d6) δ8.68, 8.21, 7.85, 5.5, 4.38, 4.23, 3.90, 1.29; HRMS (FAB) (C15H14N2O4+H) m/z 287.1035. Anal. Found (C15H14N2O4.0.12 H2O): C, 62.48; H, 5.00; N, 9.62.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccccn1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccccn1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-2-yl-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1C2C=C(C=O)C3C(=CC=CC=3)C=2C=CC=1.NC(C)(COC)CO>>[ClH:1].[CH3:25][O:20][CH2:19][C:18]([CH3:24])([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:21][OH:23]
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Reactant: O=Cc1cc2ccccc2c2ccccc12
Agent: COCC(C)(N)CO
Agent: Cl
Product: COCC(C)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (9C) gave 3-methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol hydrochloride mp 211°-213° (dec), (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:25])[CH:19]=1)[CH3:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][CH:14]([CH3:15])[C:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:27])=[O:26])=[CH:19][C:20]=1[Cl:25]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O

Procedure:
Prepared from 96a by treatment with TFA/CH2Cl2. After complete reaction, the solvent is removed in vacuo and the residue repeatedly concentrated from toluene. The resulting residue was dried under vacuum to a constant weight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][CH2:5][C:6]1[C:7]([CH3:13])=[N:8][C:9](Cl)=[CH:10][CH:11]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:26][C:25]=2[F:35])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[CH3:1][O:2][C:3](=[O:14])[NH:4][CH2:5][C:6]1[C:7]([CH3:13])=[N:8][C:9]([NH:15][C:16]2[S:17][C:18]([C:24]3[C:25]([F:35])=[CH:26][C:27]([C:31]([OH:34])([CH3:32])[CH3:33])=[CH:28][C:29]=3[F:30])=[CH:19][C:20]=2[C:21]([NH2:23])=[O:22])=[CH:10][CH:11]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COC(=O)NCc1ccc(Cl)nc1C
Product: COC(=O)NCc1ccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)nc1C

Procedure:
The title compound was synthesized from methyl[(6-chloro-2-methylpyridin-3-yl)methyl]carbamate (85 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) according to the general procedure in Example 1.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)#[N:2].[OH-:45].[Na+].OO.Cl>CS(C)=O.C(O)C>[CH3:32][O:31][C:9]1[C:8]2[C:3]([C:1]([NH2:2])=[O:45])=[N:4][C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[O:35])=[CH:6][C:7]=2[N:11]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C#N)c12
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(N)=O)c12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(4-cyano-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (70 mg, 0.121 mmol, synthesized from Intermediate 42B following Scheme 3-Step 2/Method A) was taken up in DMSO (605 μl) and Ethanol (605 μl). NaOH (1.8 ml, 1.815 mmol) was added followed by dropwise addition of hydrogen peroxide (180 μl, 2.056 mmol). The reaction was heated to 60° C. and was allowed to stir for 30 minutes. Room temperature was attained and 1N HCl was added and the products were extracted into EtOAc (3×). The organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give (R)-3-methoxy-6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxamide. The products were carried forward without purification. MS: [M+H]+ m/z 597.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:14])=[O:8]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Cl

Procedure:
Meanwhile, the 2-methylbenzoyl chloride acylating agent was prepared by suspending 4.750 g (42.2 mmol) of o-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (7.37 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[NH2:34][CH2:35][CH2:36][OH:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:34][CH2:35][CH2:36][OH:37])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCCO)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-aminoethanol, HATU and DIPEA in THF to give 338 as a colorless solid after reverse phase HPLC. MS: (ESI+) 528.0
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]2[CH:13]=[CH:14][C:15]([C:16]([O:18]C)=[O:17])=[C:3]12.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:20])[S:6][CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:3]12
Reactant: COC(=O)c1ccn2c1C(C)(C)SC2c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)SC(c2cccnc2)n2ccc(C(=O)O)c21
Temperature: 25 °C

Procedure:
A mixture of methyl 1,1-dimethyl-3-(pyrid-3-yl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate (1.1 g, 3.8 mmol), 1N aqueous NaOH (19 mmol), and methanol (40 mL) was refluxed for 17 hours. The reaction mixture was cooled to ambient temperature and taken to pH 4 with concentrated HCl. The thick solution was extracted twice with 9:1 CHCl3, isopropanol. The combined organic layers where washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow powder. The powder was triturated with ether to afford 1,1-dimethyl-3-(pyrid-3-yl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid as a pale-yellow powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-phenylpentanoic acid (0.14 g, 0.81 mmol) in anhydrous dichloromethane (5 mL) was added two drops of N,N-dimethylformamide, followed by the addition of oxalyl chloride (0.11 g, 0.89 mmol). The reaction was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to dryness to afford 5-phenylpentanoyl chloride (0.16 g, 0.81 mmol) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].C(C1C=CC=CC=1)(=O)C.C(OCC)=O.[Na].C(CC=O)(=O)C1C=CC=CC=1.Cl.CN>>[C:7]1([C:5](=[O:6])[CH:4]=[CH:3][NH:2][CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNCCC(O)c1ccccc1
Agent: CN
Agent: Cl
Agent: O=CCC(=O)c1ccccc1
Solvent: CC(=O)c1ccccc1
Solvent: CCOC=O
Product: CNC=CC(=O)c1ccccc1

Procedure:
In certain embodiments, a 3-methylamino-1-phenyl-1-propanol compound prepared by the method comprising: a) claisen condensation of acetophenone with ethyl formate leading to benzoylacetaldehyde sodium salt; b) condensation of the crude benzoylacetaldehyde sodium salt with an methylamine hydrochloride producing 1-phenyl-3-methylamino-2-propen-1-one; and c) converting 1-phenyl-3-methylamino-2-propen-1-one into 3-methylamino-1-phenyl-1-propanol by reacting 1-phenyl-3-methylamino-2-propen-1-one with sodium borohydride and acetic acid. Converting 1-phenyl-3-methylamino-2-propen-1-one into 3-methylamino-1-phenyl-1-propanol using sodium borohydride and acetic acid may comprise adding approximately 21 mmol of sodium borohydride to a solution comprising approximately 3.7 mmol of 3-methylamino-1-phenyl-2-propen-1-one in a glacial acetic acid solution producing a 3-methylamino-1-phenyl-1-propanol solution. The adding of sodium borohydride may be performed at about 1, 2, 3, 4, 5 to 10, 11, 12, 13, 14, 15° C. or more. The methods may further comprise adding approximately 240 mmol sodium hydroxide to the 3-methylamino-1-phenyl-1-propanol solution. The 3-methylamino-1-phenyl-1-propanol solution may be extracted with an ethyl acetate solution or another appropriate liquid or solution. The method may further comprise evaporating the solvent of the 3-methylamino-1-phenyl-1-propanol solution.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Reactant: COc1ccc(C=O)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A mixture of 6-Piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol, hydrochloride salt (2.0 mmol), 3-hydroxy-4-methoxy-benzaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(3-hydroxy-4-methoxy-benzyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (Compound IIb, 542 mg, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:20][C:19]1[C:14]([C:11]2([OH:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]([CH2:21][CH3:22])=[CH:17][CH:18]=1
Reactant: CCc1ccc(Cl)c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cl)c(C2(O)CCNCC2)n1
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
3-Chloro-6-ethyl-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.086 g, 0.25 mmol) was dissolved in TFA (1 mL) and DCM (1 mL). The mixture was stirred for 20 minutes and the solvent removed by evaporation under vacuum and the residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound (0.052 g). LCMS m/z 243.25 [M+H]+. R.T.=2.45 min (Analytical Method 3).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[K+].Cl[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14]>[Cl-].CO[Si](OC)(OC)CCC[N+]1C=CC(N(C)C)=CC=1>[C:1]([O:6][CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: C=C(C)C(=O)[O-]
Agent: CO[Si](CCC[n+]1ccc(N(C)C)cc1)(OC)OC
Agent: [Cl-]
Agent: [K+]
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Temperature: 135 °C
Yield: 90.6 %

Procedure:
124 g (1 mol) of potassium methacrylate were admixed with 198.5 g (1 mol) of 3-chloropropyltrimethoxysilane, 2.7 g of 1-(3'-trimethoxysilylpropyl)-4-dimethylaminopyridinium chloride and 0.5 g of N,N'-diphenyl-p-phenylamine, and the mixture was heated to 135° C. while stirring. After 1 hour at this temperature the mixture was cooled and the potassium chloride which had precipitated was filtered off and washed with 60 g of methanol. The methanol was evaporated from the combined filtrates, and the residue was distilled under reduced pressure. 225 g of 3-methacryloxypropyltrimethoxysilane having a boiling point of 82° C. (0.4 mbar) were obtained. The yield was 90.7% of theory, based on the amount of potassium methacrylate which was used. The purity of the product was 99.0%. In the gas chromatogram only traces of 4-dimethylaminopyrrdine were detectable. A 2% solution of the product in water with a pH of 4 contained no oily separation of any kind.
Reaction SMILES: O[CH:2]1[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.CCCCCC>[CH3:17][C:16]([CH3:18])([CH3:19])[CH2:15][C:14]([NH:13][C:8]1[C:7]([CH3:21])=[C:6]([CH3:2])[C:5]2[O:4][C:3]([CH3:23])([CH3:22])[CH:11]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[C:9]=1[CH3:12])=[O:20]
Reactant: C1CCNC1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(N1CCCC1)C(C)(C)O2
Yield: 36 %

Procedure:
Using N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 234 and pyrrolidine, the title compound was synthesized in the same manner as in Example 297. Yield: 36%. Melting point: 197-198° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)[CH:13]([CH3:15])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)COc1cccc(B(O)O)c1
Product: CC(C)COc1cccc(-c2cccn3nc(Cl)nc23)c1

Procedure:
2-Chloro-8-(3-isobutoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-isobutoxyphenylboronic acid in a manner analogous to Example 2c (0.39 g, 60%). MS=302 (MH)+.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[N:18][C:17]=1[NH2:23])C.[OH-].[Na+]>O>[NH2:23][C:17]1[C:16]([CH2:15][OH:14])=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1
Reactant: CCOC(=O)c1ccc(C)nc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a tetrahydrofuran (12 mL) solution of lithium aluminum hydride (706 mg, 14.9 mmol, purity: 80%) was added 2-amino-6-methyl-nicotinic acid ethyl ester (670 mg, 3.72 mmol) described in Manufacturing Example 170-1-2 at 0° C., which was stirred for 30 minutes at room temperature. Water (706 μL), a 5 N sodium hydroxide aqueous solution (706 μL), and water (2.12 mL) were added to the reaction mixture in that order at 0° C., which was filtered through a Celite pad. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (379 mg, 74%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([CH2:28][C:29](O)=[O:30])=[N:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:30])=[N:20]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1noc2ccccc12)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(1,2-benzoxazol-3-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.32 (d, J=7.9, 1H), 8.07-7.97 (m, 3H), 7.95-7.89 (m, 1H), 7.76 (d, J=8.4, 1H), 7.69 (ddd, J=8.3, 7.0, 1.1, 1H), 7.48-7.41 (m, 1H), 4.19 (s, 2H), 3.86-3.80 (m, 4H), 3.16-3.07 (m, 4H); MS (ESI+) M/Z 406 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][CH:41]([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]([F:51])[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1ccccc1C(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(difluoromethyl)phenyl)boronic acid gave 335. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.09-7.80 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.71-7.66 (m, 2H), 7.65-7.59 (m, 1H), 7.59-7.50 (m, 3H), 4.75 (dd, J=10.6, 3.8 Hz, 1H), 4.42-4.26 (m, 1H), 4.19-4.07 (m, 1H), 4.04-3.87 (m, 1H), 3.79 (s, 3H), 3.21-3.08 (m, 1H), 2.08-1.99 (m, 1H), 1.97-1.85 (m, 1H), 1.74-1.58 (m, 4H). LCMS (ES+) m/z 481 (M+1).
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])[S:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])[S:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2cc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)cs2)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2cc(-c3cccc4c3CCC4O)cs2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Prepared using General Procedure 3. To a solution of 5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile (17 mg, 0.03 mmol) in THF (1 mL) was added 1M solution of TBAF in tetrahydrofuran (0.3 mL, 0.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by preparative HPLC to yield 8 mg (46%) of 5-(4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 226 as white solid. LCMS-ESI (m/z) calculated for C23H21NO2S: 375.1; found 398.1 [M+Na]+. tR=3.84 min; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=2.3 Hz, 1H), 7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.35-7.28 (m, 1H), 7.26 (d, J=1.4 Hz, 1H), 7.24 (s, 1H), 7.06-6.89 (m, 1H), 5.29 (t, J=6.1 Hz, 1H), 4.77-4.49 (m, 1H), 3.20 (ddd, J=16.0, 8.4, 4.7 Hz, 1H), 3.01-2.86 (m, 1H), 2.50 (dddd, J=13.0, 8.1, 6.8, 4.7 Hz, 1H), 2.11-1.88 (m, 1H), 1.58 (s, 1H), 1.41 (d, J=6.1 Hz, 6H); 13 NMR (101 MHz, CDCl3) δ 159.51, 146.35, 142.55, 142.00, 140.88, 133.16, 131.79, 131.24, 128.14, 127.69, 127.56, 124.16, 123.54, 122.06, 116.54, 114.39, 103.84, 76.68, 72.45, 36.28, 30.50, 22.08.