Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[O-:13][S:14]([O-:16])=[O:15].[Na+].[Na+].O>CCO>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([S:14]([OH:16])(=[O:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Yield: 73.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 1,4-difluoro-2-methyl-5-nitrobenzene (1.2 g, 6.93 mmol) in EtOH (10 ml) and Na2SO3 (1.98 g, 15.7 mmol) in EtOH:water (40 ml:25 ml) at 70° C. for 16 h gave the title compound (1.2 g, 73%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10]Br>C(=S)=S>[Br:10][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9]
Reactant: COc1cccc(O)c1
Reactant: BrBr
Solvent: S=C=S
Product: COc1ccc(Br)c(O)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixed solution of 25 g of 3-methoxyphenol and 100 ml of carbon disulfide (CS2) was added dropwise 10.3 ml of bromine at room temperature. After stirring the mixture for 30 minutes, the solvent was removed under reduced pressure, and water was added to the residue. The reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure to give 34.8 g of 2-bromo-5-methoxyphenol (yield: 85%, boiling point: 96°-98° C. (4 mmHg), colorless oily product).
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.O1CCCC1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.Cl>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)(=[O:24])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccs4)c3[nH]2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of ethyl (2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (300 mg), tetrahydrofuran (5 mL), ethanol (5 mL) and 2N aqueous sodium hydroxide solution (4 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained solid was washed with ethyl acetate to give the title compound (278 mg, yield 98%) as a white solid. melting point 121-123° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11](OC)=[N:10]1.[Cl-:18].[NH4+:19]>>[ClH:18].[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:9]1[NH:10][C:11](=[NH:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: [NH4+]
Reactant: COC1=NC(CCC2OCCCO2)CCCC1
Reactant: [Cl-]
Product: Cl
Product: N=C1CCCCC(CCC2OCCCO2)N1

Procedure:
The product of Example 112 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[Br:1][C:2]1[C:3]([CH:7]([CH3:9])[CH3:8])=[N:4][N:5]([CH2:10][OH:11])[CH:6]=1
Reactant: CC(C)c1n[nH]cc1Br
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
The mixture of 1.88 g of 4-bromo-3-i-propyl-1H-pyrazole, 0.60 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.29 g of 4-bromo-3-i-propyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[N:4][N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:25][CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[N:4][N:3]=[C:2]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:27][CH2:28]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(-c3ccccc3OC)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccccc3OC)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(2-methoxyphenyl)phthalazine described with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: CC1C=CC(N=C=O)=CC=1[N:11]=[C:12]=[O:13].C[OH:15].[CH:16]1C([NH2:22])=CC=C(S(C2C=CC(N)=CC=2)(=O)=O)[CH:17]=1>C(C(C)=O)C>[NH2:22][C:12]([NH2:11])=[O:13].[NH2:11][C:12]([O:13][CH2:16][CH3:17])=[O:15]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Nc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Reactant: CO
Solvent: CCC(C)=O
Product: CCOC(N)=O
Product: NC(N)=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 269.1 %

Procedure:
To 17 g of 2,4-toluene diisocyanate was added 40 g of methyl ethyl ketone as a solvent, followed by adding dropwise thereto 3.8 g of methanol, and the reaction was carried out with stirring at 60° C. for 5 hours. Then, 9.9 g of 4,4′-diaminodiphenyl sulfone was added thereto, and the reaction was carried out with stirring at 60° C. for 4 hours. After completion of the reaction, the methyl ethyl ketone as solvent was removed by the use of an evaporator, and the residue was dried overnight in a vacuum to obtain 16 g of a urea-urethane composition as white crystals. The melting point of the white crystals was 169° C. In IR analysis on the crystals, characteristic peaks due to a urea-urethane compound appeared at 1660 cm−1 and 1740 cm−1. The content of the urea-urethane main constituent in the urea-urethane composition was 52% as measured by liquid chromatography.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([C:7]([C@@:9]([C:25]([OH:27])=[O:26])([OH:24])[C@@:10]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])([OH:14])[C:11]([OH:13])=[O:12])=[O:8])=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:49][C:43]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:41]3[C:42]=2[C@:33]2([C@@H:39]([O:40]3)[CH2:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:32][CH2:31]1>C(O)C>[CH3:29][N:30]1[CH2:49][C:43]2=[C:42]3[C:41](=[C:46]([O:47][CH3:48])[CH:45]=[CH:44]2)[O:40][C@H:39]2[C@@:33]3([CH:34]=[CH:35][C:36]([CH2:38]2)=[O:37])[CH2:32][CH2:31]1.[C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([C:7]([C@@:9]([C:25]([O-:27])=[O:26])([OH:24])[C@@:10]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:16])([OH:14])[C:11]([O-:13])=[O:12])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Reactant: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Product: COc1ccc2c3c1O[C@@H]1CC(=O)C=C[C@]31CCN(C)C2
Product: Cc1ccc(C(=O)[C@](O)(C(=O)[O-])[C@@](O)(C(=O)[O-])C(=O)c2ccc(C)cc2)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Di-p-toluoyl-L-tartaric acid (1.35 g, 3.50 mmol) was dissolved in ethanol (10 ml) on heating to 40° C. and then synthetic racemic narwedine (1.00 g, 3.50 mmol) was added and the mixture was heated at reflux for 1 h then cooled to 40° C. and stirred for 16 hours at this temperature. The mixture was cooled to ambient temperature, stirred for 2 h and then the white solid was isolated by filtration to give the 1:1 diastereomeric salt [(+)−narwedine] [di-p-toluoyl-L-tartrate] (2.16 g, 92% yield, 96% e.e.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cncc(Br)c1
Reaction time: 16 h
Yield: 95.7 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-ethanone (3.0 g, 15 mmol) is dissolved in MeOH (20 mL) and sodium borohydride (1.1 g, 30 mmol) is added in 5 small portions every 15 min. The mixture is stirred for 16 hrs and the solvent is then removed in vacuo. Saturated aqueous NH4Cl solution (10 mL) is added along with 30 mL of water. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 2.9 g of 1-(5-bromo-pyridin-3-yl)-ethanol.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:17][C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(C2CCCC2)cc1F
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-cyclopentyl-2-fluorobenzene-1-sulfonyl chloride, 134 (0.06 g; 0.21 mmol) in dichloromethane (1 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.033 g; 0.21 mmol) was added followed by pyridine (0.033 g; 0.42 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (10 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as an off-white solid (34 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1ccc(-c2cc(C)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, grey solid (38 mg, 67%), MS (ISP) m/z=307.5 [(M+H)+], mp 245° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-methoxy-phenylboronic acid (36.8 mg, 0.24 mmol).
Reaction SMILES: [CH:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:27]
Reactant: O=C(OCc1ccccc1)C(CCCCCCCCI)C1CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A mixture of the iodoester from step 2, (3.99 g, 8.7 mmol) and sodium cyanide (0.47 g, 9.6 mmol) in 15 mL of anhyd. DMSO was heated at 70-75° C. for 30 min. After cooling, the reaction mixture was poured over ice (~ 40 g), extracted into ether and washed successively with water and saturated brine. The organic layer was concentrated to yield an oil (2.89 g). 1H NMR (300 MHz, CDCl3). δ: 7.35 (m, 5H), 5.15 (s, 2H), 2.30(t, 8 Hz, 2H), 2.20(m, 1H), 2.00(m, 1H), 1.3-1.8 (m, 22H).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:10][P:11](Cl)Cl.[ClH:14]>O.O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:10]([PH2:11])[C:3]2[CH:8]=[CH:7][C:6]([Cl:14])=[CH:5][CH:4]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: Cl
Reactant: CP(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: PC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
To 12.6 g. of magnesium turnings was gradually added a solution containing 96 g. (0.50 mole) of p-chlorobromobenzene and 180 cc. tetrahydrofuran. The reaction mixture was stirred and maintained under a nitrogen atmosphere during the addition, following which the contents of the vessel were heated to reflux temperature for two hours. When the reaction mixture had cooled, a solution of methyldichlorophosphine (29.3 g., 0.25 mole) in 25 cc. tetrahydrofuran was gradually added. Following completion of this addition the reaction mixture was heated to reflux temperature for two hours. When the mixture had cooled it was slowly poured into 500 cc. of cold water and then acidified to a pH of 5 using aqueous hydrochloric acid. The resultant aqueous solution was extracted using chloroform. The organic layer was then dried over anhydrous magnesium sulfate and the chloroform removed under reduced pressure. The residue remaining following removal of the chloroform weighed 64 g. and was distilled, the fraction boiling at between 155 and 160 under a pressure of 0.5 mm. Hg being collected. This distillate converted to a white solid upon cooling. The solid material weighed 34 g. and exhibited the following analysis:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](OC)[C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(OC)c2c[nH]c3ncccc23)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncccc23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-[(4-Benzyloxy-3-methoxy-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (565, 0.9 g, 2.4 mmol) and acetonitrile (50 mL) were mixed with trifluoroacetic acid (0.360 mL, 4.7 mmol) and triethylsilane (0.746 mL, 4.7 mmol). The reaction was heated at 80° C. and stirred overnight. The reaction was concentrated. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography to give the compound (P-1613, 0.454 g 54.8%). MS (ESI) [M+H+]+=345.3.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[CH2:3][CH:4]=[CH2:5].C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[CH2:3][CH:4]1[CH2:5][O:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C)(C)CC
Solvent: ClCCl
Product: CCC(C)(C)CC1CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,4-dimethylhex-1-ene (49.5 g, 442 mmol) in methylene chloride (1 L) at 0° C. was added m-CPBA (120 g, 535 mmol), and the reaction was stirred at rt for 16 h. The reaction mixture was filtered through Celite and the filtrate was washed with saturated sodium hydrogen sulfite (1×1 L), saturated sodium carbonate (2×1 L), dried over sodium sulfate and concentrated to give 2-(2,2-dimethylbutyl)oxirane, which was dissolved in methanol (400 mL). To this solution was added sodium azide (22.8 g, 351 mmol), ammonium chloride (18.8 g, 351 mmol) and water (100 mL). After heating at 80° C. overnight, the volatiles were removed and the residue was partitioned between water (300 mL) and ethyl acetate (300 mL). The organic layer was separated, dried over sodium sulfate and concentrated, and the residue was purified by passing through a silica gel pad (13 cm×10 cm) eluted with 1:9 ethyl acetate/hexanes to provide 1-azido-4,4-dimethylhexan-2-ol. 1H NMR (500 MHz, CDCl3) δ 3.88 (m, 1H), 3.29 (dd, J=12.2 Hz, J=3.7 Hz, 1H), 3.23 (dd, J=12.2 Hz, J=7.7 Hz, 1H), 1.90 (d, J=4.5 Hz, 1H), 1.40 (dd, J=14.7 Hz, J=8.2 Hz, 1H), 1.28 (m, 3H), 0.93 (m, 3H), 0.90 (s, 3H), 0.83 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.[Li]CCCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:21](=[O:23])[CH3:22])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ccc(Cl)nc12
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To a solution of 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 10.0 g, 41.2 mmol) in 200 mL THF in a dry ice/acetone bath was added nBuLi solution (2.5 M in hexanes; 18.14 ml, 45.4 mmol) slowly (dropwise) via addition funnel such that the internal temperature did not exceed −72° C. After 15 min, N-methoxy-N-methylacetamide (Aldrich; 5.05 ml, 49.5 mmol) was added via syringe such that the internal temperature did not exceed −72° C. The dry ice/acetone bath was removed and the reaction was quenched with 200 mL saturated aq. NH4Cl and diluted with 300 mL Et2O. The organic layer was washed 1× brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (240 g column) using 0-20% EtOAc/hexanes until less polar impurities elute, then 20-40% EtOAc/hexanes to elute desired material. Fractions were combined and concentrated to give 1-(2-chloroquinolin-8-yl)ethanone (3.63 g, 17.65 mmol, 43% yield) as a peach-colored solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, d, J=8.6 Hz), 8.06 (1H, dd, J=7.2, 1.6 Hz), 7.96 (1H, dd, J=8.0, 1.6 Hz), 7.59-7.66 (1H, m), 7.46 (1H, d, J=8.6 Hz), 2.98 (3H, s). m/z (ESI, +ve) 206.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H]1CCCN(C(OC(C)(C)C)=O)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C@@H:43]5[CH2:44][CH2:45][CH2:46][NH:47][CH2:42]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-tert-butyl 3-aminopiperidine-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.52 (m, 2H) 1.52-1.77 (m, 7H) 1.85-1.99 (m, 3H) 2.45 (t, J=9.9 Hz, 2H) 2.85 (d, J=12.4 Hz, 1H) 3.01 (dd, J=11.8, 3.4 Hz, 1H) 3.32 (s, 3H) 3.85 (m, 1H) 3.94 (s, 3H) 4.05 (t, J=14.0 Hz, 3H) 4.76 (quin, J=8.2 Hz, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H) 7.97 (s, 1H) 8.04 (d, J=7.8 Hz, 1H) 8.26 (s, 1H) 8.28 (d, 1H). [M+H] calc'd for C26H33F2N7O3, 530. found 530.
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH2:14]C(O)=O)[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56])[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:35])C=C>>[CH2:1]([C:8]1[N:13]([CH2:14][C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O
Product: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COCc1ccccc1Cl

Procedure:
N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl)acetyl-3-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (90) was prepared from 52b and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenyl-methoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR (DMSO-d6) δ 9.2 (s, 1H), 8.75 (d, 1H), 7.7-7.1 (m, 14H), 6.4 (d, 1H), 4.65 (d, 6H), 4.56 (s, 1H), 4.6-4.35 (dd, 1H), 3.9 (s, 2H), 2.9-2.6 (m, 6H)
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][OH:22].Cl>CN(C1C=CN=CC=1)C.ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:22][CH2:21][CH2:20][O:19][CH3:18])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To tosyl chloride (50.0 g, 0.263 mol) at 0° C. and under nitrogen were added anhydrous dichloromethane (80 ml), anhydrous pyridine (23 ml, 24.3 g, 0.29 mol), 2-methoxyethanol (21.0 ml, 20.0 g, 0.263 mol) and a catalytic quantity of DMAP. After 10 minutes the mixture was warmed to room temperature, at which it was stirred for 16 hours. Dichloromethane (100 ml) and 1 M aqueous hydrochloric acid (50 ml) were added. The organic layer was isolated and washed with 1 M aqueous hydrochloric acid (4×30 ml) and water (4×30 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (51.68 g, 85%) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:9][CH2:10][CH3:11].[CH3:12][C:13]1[C:14]([CH3:23])=[C:15]([OH:22])[C:16]([CH3:21])=[N:17][C:18]=1C=C.C(=O)=[O:25]>O>[CH3:21][C:16]1[C:15]([OH:22])=[C:14]([CH2:23][OH:25])[C:11]([CH2:10][OH:9])=[C:18]([CH:13]=[CH2:12])[N:17]=1
Reactant: C=Cc1nc(C)c(O)c(C)c1C
Reactant: CCOCC
Reactant: O=C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: C=Cc1nc(C)c(O)c(CO)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.15 moles of lithium aluminum hydride in 250 ml. of ether is added dropwise with stirring a solution of 0.05 moles of dimethyl 2-methyl-3-hydroxy-6-vinylpyridine, 4,5-dicarboxylate in 150 ml. of ether. The mixture is refluxed for 6 hours and stirred overnight at room temperature. The reaction mixture is cooled and 100 ml. of water added dropwise with stirring. The resulting mixture is saturated with carbon dioxide for 30 minutes and then filtered. The precipitate is stirred with 250 ml. of ethanol-water (1:1) and saturated again with carbon dioxide and filtered. The solid is then extracted twice with 100 ml. of boiling ethanol. The combined filtrates are evaporated to dryness in vacuo. The residue is extracted 5 times with 100 ml. of boiling ethanol. The combined extracts are filtered and evaporated to dryness to give 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)-6-vinylpyridine.