Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Si:23]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=[C:2]([Cl:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (142 mg, 0.671 mmol, Example 121, Step A) in methylene chloride (1.0 mL) at 0° C. was added 1H-imidazole (55 mg, 0.80 mmol) followed by tert-Butylchlorodiphenylsilane (190 μL, 0.74 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The reaction was stirred with warming to room temperature for 64 hours. The reaction mixture was diluted with diethyl ether and was washed with water followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-4% EtOAc in hexanes afforded product as a white solid (0.20 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 4H), 7.55-7.34 (m, 8H), 4.77 (s, 2H), 1.12 (s, 9H); 19F NMR (282 MHz, CDCl3) δ−68.49 (s); LCMS (M+H)+: 450.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[S:33][CH2:34][CH2:35][N:36]=1.Cl.C([O-])(O)=O.[Na+]>COCCO>[S:33]1[CH2:34][CH2:35][N:36]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CSC1=NCCS1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 120 °C
Reaction time: 13 h
Yield: 58.4 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}-acetamide (200 mg), 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (62 mg), concentrated HCl (0.064 ml) and 2-methoxyethanol (3 ml) was stirred at 120° C. for 13 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent to give N-{4-{2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (139.8 mg) as a pale yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30]C(=O)C)[CH:10]=1.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][S:37]([CH:34]2[CH2:36][CH2:35]2)(=[O:39])=[O:38])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1

Procedure:
The compound was prepared from the compound of Example 1 using the procedures of Example 2 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.88 (s, 1H), 8.23 (s, 1H), 8.0 (s, 1H), 7.96 (s, 1H), 7.76-7.64 (m, 3H), 7.6 (s, 2H), 7.5-7.46 (m, 2H), 7.3-7.25 (m, 1H), 3.88 (s, 3H), 2.88-2.85 (m, 1H), 1.02-1.0 (m, 4H); LC-MS (ESI): Calculated mass: 505.54; Observed mass: 506.1 [M+H]+ (rt: 1.517 min).
Reaction SMILES: Cl.[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH:13]([NH2:14])[C:7]=2[CH:6]=1)(=[O:4])[CH3:3].[O-:15][C:16]#[N:17].[K+]>O>[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH:13]([NH:14][C:16]([NH2:17])=[O:15])[C:7]=2[CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1cc2c(s1)CCCC2N
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)c1cc2c(s1)CCCC2NC(N)=O
Temperature: 70 °C

Procedure:
A sample of 6.3 grams of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is dissolved in 35 ml. of water and cooled to 15° C. A solution of 2.64 grams of potassium cyanate in 35 ml. of water is added, and after 0.5 hour the mixture is heated at 70° C. for about 40 minutes. The mixture is cooled, and the solid is collected and washed with water. On drying, 5.55 grams, melting point 218° C. to 220° C., of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is obtained.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]2[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[CH2:31]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]3[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH2:31]2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)cn5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 60.9 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 19A) and 0.21 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 39 mg (33% of theory) of the product as a solid.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O-2].[Mg+2].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:13].S(=O)(=O)(O)O>O.CCOCC>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(OC(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
In this example, 11.5 g L-proline and 8.0 g magnesium oxide are dissolved in 100 ml water, and then admixed with 60 ml ether. A solution of p-methylphenyl chloroformate [8.5 g; boiling point: 109°-110° C. (28-30 mmHg)] dissolved in 50 ml ether is added thereto, while cooling the mixture in an ice bath (5°-10° C.). After stirring for 30 minutes, the reaction solution is acidified by adding 60 ml concentrated sulfuric acid, and extracted three times with 60 ml ethyl acetate. The extract is washed three times with 40 ml 2N HCl and four times with 50 ml water, and then dried overnight over anhydrous sodium sulfate (30 g). After drying, the extract is filtered, and the filtrate is concentrated under reduced pressure. The resulting oily materials are admixed with 100 ml n-hexane, and left standing in a refrigerator (about -15° C.). The deposited crystals are filtered, and recrystallized from ethyl acetate-n-hexane (1:1 by volume), whereby p-methylphenyloxycarbonyl-L-proline (compound number 8; 9.25 g; mp: 76°-77° C.) is obtained. Yield: 74.3%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1)#[CH:2].Br[CH2:13][CH2:14]Cl.[OH-].[Na+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: ClCCBr
Reactant: C#Cc1ccc(CC#N)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C#Cc1ccc(C2(C#N)CC2)cc1
Temperature: 50 °C
Yield: 92.7 %

Procedure:
A mixture of (4-ethynylphenyl)acetonitrile (1.0 g, 0.0071 mol), 1-bromo-2-chloro-ethane (1200 μL, 0.014 mol), benzyltriethylammonium chloride (0.1 g, 0.0004 mol) and 1 ml of 50% NaOH water (w/v) was heated at 50° C. for 4 hours. The product was extracted with EtOAc and the combined organic phases were washed with water and brine successively, dried over Na2SO4, filtered, and concentrated in-vacuo to afford 1.1 g of the desired product, which was used in the following step without further purification.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O>[C:16]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Reaction time: 8 h

Procedure:
A 500 ml, round-bottom, three-neck flask was charged with 300 ml of water, 33.55 g (0.40 mole) of sodium bicarbonate, and 19.33 g (0.14 mole) of p-aminobenzoic acid (PABA). The resultant solution was stirred mechanically as 25.0 ml (30.0 g, 0.18 mole) of carbobenzoxy chloride was added dropwise over a period of one hour. Once addition was complete, the thick, white suspension which had formed was allowed to stir overnight. This suspension was suction filtered, and further work-up of both the filtrate (A), and the filtered solid (B) afforded the desired product. The filtrate (A) was acidified with concentrated hydrochloric acid to pH 1, and the white precipitate which formed was isolated by filtration and washed with water until the filtrate was neutral. This precipitate was dissolved in 1 N NaOH and extracted with 100 ml of ether. The ether layer was back extracted twice with 60 ml of 1 N NaOH and these extracts were pooled with the first aqueous layer. Acidification of the pooled basic layer to pH 1 yielded a copious white precipitate which was collected on a filter and washed with water until the filtrate was neutral. The moist solid was freed of water by dissolving it in ethyl acetate (EtOAc, 200 ml), draining off the several milliliters of water which rapidly settled out, drying over magnesium sulfate, and taking the colorless solution to dryness in vacuo. Yield 6.05 g of Z-PABA-OH as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2.[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH:6]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]2
Reactant: CCCCC1Cc2cc(N)c(F)cc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(N)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
A solution of 5-amino-2-butyl-6-fluoro-1-indanone (5.14 g, 23.2 mmol) in N,N-dimethylformamide (23 mL) was placed under a nitrogen atmosphere and treated with N-chlorosuccinimide (3.2 g, 24 mmol). After stirring at room temperature for 3 hours, the reaction mixture was partitioned between EtOAc and water. The organic portion was washed with water and brine, dried over MgSO4, filtered, and evaporated under vacuum to an orange solid (6.5 g). The crude product was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to afford 5-amino-2-butyl-4-chloro-6-fluoro-1-indanone (5.2 g, 88%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N-:12][C:13](=[O:16])[CH2:14][Br:15])=O)(C)(C)C.[ClH:17]>C(OCC)(=O)C>[ClH:17].[Br:15][CH2:14][C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH2:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCC[N-]C(=O)CBr
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCNC(=O)CBr

Procedure:
3.1 g (10.5 mmol) of [3-[N-(tert-butoxycarbonyl)amino]propyl]-N-(bromoacetyl)-amide (Example 49a) is stirred with 50 mmol. of 1M hydrochloric acid in ethyl acetate for five hours at room temperature. The product is suctioned off, and the solid is rewashed with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]#[C:34][CH2:35][OH:36])[CH:3]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl.C(OCC)(=O)C>[CH3:44][S:45]([O:36][CH2:35][C:34]#[C:33][C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:47])=[O:46]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCO)c(OCc1ccccc1)c2=O
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of intermediate 182, N-(4-fluoro-2-(3-hydroxyprop-1-ynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.280 g, 0.57 mmol) and triethylamine (0.12 ml, 0.86 mmol) in dichloromethane (5 ml) was cooled to 0° C., treated drop wise with methanesulfonyl chloride (0.050 ml, 0.64 mmol) and then stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (75% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.65 (6H, s, 2×CH3), 3.10 (3H, s, SCH3), 4.05 (4H, m, 2×CH2), 4.67 (2H, d, J=6.1 Hz, NCH2), 5.03 (2H, s, CH2), 5.29 (2H, s, OCH2), 7.07 (1H, m, aromatic), 7.18 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.32–7.36 (3H, m, aromatics), 7.38 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 7.49–7.51 (2H, m, aromatics), 7.77 (1H, broad t, NH). MS (ESI+) m/e 570 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][C:11]([CH3:52])=[CH:12][C:13]=1[C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:39]=2)=[O:36])[C:18]1=[O:51])=[O:15]>C(Cl)Cl>[CH3:8][C:9]1[S:10][C:11]([CH3:52])=[CH:12][C:13]=1[C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:35](=[O:36])[NH:37][C:38]2[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=2)[C:44]([OH:46])=[O:45])[C:18]1=[O:51])=[O:15]
Reactant: Cc1cc(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(C(=O)OC(C)(C)C)c3)CN(C3CCCCC3)c3ccccc32)c(C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(C(=O)O)c3)CN(C3CCCCC3)c3ccccc32)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea (450 mg) in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethanol was added to the residue, crystals were collected by filtration, to thereby obtain 202 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH:14]=[C:15]([NH:17][CH3:18])[CH3:16].N1C=CC=CC=1.Cl.N1C=CC=CC=1>C1COCC1>[CH3:11][O:12][C:13](=[O:19])[CH:14]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)/[C:15](=[N:17]/[CH3:18])/[CH3:16]
Reactant: CNC(C)=CC(=O)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Bromobenzoyl chloride (17.14 g, 78.1 mmol) and 3-methylamino-but-2-enoic acid methyl ester (10.0 g, 78.1 mmol) were combined in THF (600 mL) and cooled to 0° C. Pyridine (6.8 mL, 85.9 mmol) was added by syringe, and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride was observed on the flask walls, so the solution was decanted and then concentrated to 10% of its original volume. The residue was diluted with EtOAc (400 mL) and washed twice with H2O. The organic layer was dried, filtered, and concentrated to give the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](CF)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.26 ml of triethylamine and 2 ml of glacial acetic acid were mixed with 0.34 g of 4. The mixture was cooled to 0° C. and 0.21 ml of acetic anhydride was added drop-by-drop to the stirred mixture. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solvents were evaporated under reduced pressure, the residue was triturated with a mixture of ethyl acetate and ether and filtered. The filtrate was eluted through a florisil pad, using ethyl acetate as eluent. The solvent was evaporated under reduced pressure to give 6, as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@@H:5]([C@H:7](OS(C)(=O)=O)[C@@H:8]2[C@H:12]([CH2:13]OS(C)(=O)=O)[O:11][C:10]([CH3:20])([CH3:19])[O:9]2)[CH2:4][O:3]1.[S-2:27].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:26])[O:6][C@@H:5]([C@@H:7]2[C@@H:8]3[C@@H:12]([O:11][C:10]([CH3:20])([CH3:19])[O:9]3)[CH2:13][S:27]2)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]([C@@H](OS(C)(=O)=O)[C@H]2COC(C)(C)O2)[C@H](COS(C)(=O)=O)O1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H]([C@H]3COC(C)(C)O3)SC[C@@H]2O1
Yield: 94.4 %

Procedure:
10.1 g (0.024 mol) of methanesulfonic acid {(4R)-(2,2-dimethyl[1,3]dioxolan-4-yl)}-{(4S,5S)-(5-methanesulfonyloxymethyl-2,2-dimethyl[1,3]dioxolan-4-yl)}-(S)methyl ester from the aforementioned Experimental Example 3 were dissolved in 260 mL of N,N-dimethylformamide, and 8.9 g (0.036 mol) of sodium sulfide were added. The reaction mixture was reacted at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure, and water was added to the concentrate, which was then extracted with ethyl acetate. The organic layer was dried and filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using the eluant (hexane:ethyl acetate=5:1) to obtain 5.9 g (yield: 94%) of (3aS,4R,6aR)-4-((4R)-2,2-dimethyl[1,3]dioxolan-4-yl)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[NH2:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A 100-mL round-bottom flask was a solution of methyl 2-aminobenzoate (1 g, 6.62 mmol, 1.00 equiv) in HCl (30%, 10 mL). To this solution was added a solution of NaNO2 (500 mg, 7.25 mmol, 1.02 equiv) in H2O (10 mL) dropwise at 0° C. over 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Then, a solution of SnCl2.2H2O (2.75 g, 12.19 mmol, 2.00 equiv) in HCl (30%) (12 mL) was added dropwise at 0° C. The resulting solution was stirred for an additional 2 hours at room temperature. The solids were collected by filtration and washed with H2O (2×20 mL) affording methyl 2-hydrazinylbenzoate as white solid (0.6 g, 55%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].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>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2ccnc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of quinoline-4-carboxylic acid (301 mg, 1.74 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (357 mg, 1.74 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (8 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-70% EtOAc in heptane) to give a pure product (49) as a pale yellow solid (370 mg, 59%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].CN(C)C=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1>O.CCOC(C)=O.CCCCCC>[Br:12][C:13]1[CH:18]=[C:17]([S:1][CH2:2][CH2:3][OH:4])[CH:16]=[N:15][CH:14]=1
Reactant: OCCS
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-mercaptoethanol (3.30 g, 42.21 mmol), sodium hydroxide (1.69 g, 42.21 mmol) and N,N-dimethylformamide (50 mL) was stirred at ambient temperature for 4 h. The resulting solution was cooled to 0-5° C. and 3,5-dibromopyridine (8.00 g, 33.77 mmol) was added in one portion. The mixture was stirred at 0-5° C. for 20 min, warmed to ambient temperature and further stirred for 1 h. TLC analysis on silica gel eluting with EtOAc-hexane (3:1) indicated an incomplete reaction. Therefore, the mixture was heated at 75° C. (oil bath temperature) for 1 7 h. After cooling to ambient temperature, the mixture was poured into water (250 mL) and extracted with ether (3×75 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated (rotary evaporator) to a light-yellow oil. The oil was vacuum distilled using a short-path distillation apparatus to afford 4.55 g (57.5%) of a light-yellow oil, bp 138-140° C. at 0.35 mm Hg.