Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:19]2[N:20]=[C:21](O)NC=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:25]1C=CC=C[CH:26]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:19]2[NH:20][CH:21]=[CH:26][N:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccncc1
Reactant: Oc1nc(-c2ccccc2)c[nH]1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To 177 mg (0.148 mmol) of phenyl hydroxy imidazole (from Step 1) and 50 μL of pyridine in 1.5 mL of methylene chloride at 0° C. was added 32 μL of thionyl chloride, and the resulting brown solution was stirred at room temperature for 2 hour. The reaction mixture was washed with water, dried and concentrated in vacuo. The residue was purified over silica gel to give 105 mg (92%) of conjugated phenyl imidazole biphenyl as an oil which solidified upon standing.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O:17][CH2:18][CH3:19])=[O:20])[CH3:16]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC

Procedure:
A solution of methyl 4-(bromomethyl)benzoate (12.5 g, 54.6 mmol) in triethyl phosphite (20 mL, 114 mmol) was heated at 150° C. for 2 hours. After cooling, the solution was concentrated under vacuum. Purification by chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound. MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[C:12]1([C:18]([CH2:20][CH2:21][C:22]#[CH:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[OH:19][C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: C#CCCC(=O)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCCC(O)(c1ccccc1)C1SCCCS1
Reaction time: 1.25 h
Yield: 75 %

Procedure:
1,3-Dithiane (3.8 g, 31.6 mmol) was stirred in 120 mL of tetrahydrofuran at -40° C. under argon and 13.2 g (33 mmol) of 2.5M n-BuLi in hexane was added. After 10 minutes the temperature was adjusted to -20° C. and 1.25 hours later 2.27 g (14.36 mmol) of but-3-ynyl phenyl ketone was added as a solid. Stirring was continued for 20 minutes before placing in a freezer at -20° C. for 20 hours. The mixture was then poured onto water, the layers were separated, and the aqueous portion extracted with methylene chloride (3×30 mL). The combined organics were washed with brine, dried (MgSO4) and solvents evaporated at reduced pressure. The residue was chromatographed on 75 g silica (98:2, hexane:EtAc, then 4%, 10%, and 20% EtAc) to give 3.0 g (75%) of product.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:38])[C@@H:18]([NH:26][C:27](=[O:37])[C@H:28]([CH:34]([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:48](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:48])[CH2:16][C@H:17]([OH:38])[C@@H:18]([NH:26][C:27](=[O:37])[C@H:28]([CH:34]([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1)C(C)C
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1)C(C)C
Reaction time: 3.5 h

Procedure:
Analogously to Example 37f), 30 ml of 4M HCl in dioxane are added to 3.5 g (5.65 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 5 ml of DMF. After 3.5 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.53 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.00; FAB MS (M+H)+ =520.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Diethanolamin were converted to yield 2-[{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol, MS: 405 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([N:13]=[C:14]=[O:15])([F:12])[F:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH:13][C:10]([F:12])([F:11])[F:9])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C=NC(F)(F)F
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)NC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloroaniline (64 grams; 0.5 mol) in toluene (100 ml) is placed into a suitable pressure vessel, and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (56 grams; 0.5 mol) is added thereto and the pressure vessel is sealed. The reaction mixture is allowed to warm up to room temperature and stand for a period of about 24 hours. After this time the pressure vessel is opened and the contents are stripped of toluene under reduced pressure. The residue is recrystallized to yield N-(4-chlorophenyl)-N'-trifluoromethyl urea.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[O:46]COC)=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:26])([F:27])[F:25])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[OH:46])=[CH:33][CH:34]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COCOc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3O)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (40-2), Example (51-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (1.66 g, 3.93 mmol) obtained in Example (28-5) and methyl [4′-hydroxy-2-(methoxymethoxy)-1,1′-biphenyl-4-yl]acetate (990 mg, 3.28 mmol), the title compound was obtained as a colorless amorphous compound (111 mg, yield: 7%).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: O=C1N(CCN2CCOCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 190° C. and MS: m/e=483.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and N-(2-chloroethyl)-morpholine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:32](OCC)(OCC)OCC>O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]3[C:15]([N:24]4[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]4)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)=[O:11])=[CH:3][C:2]=2[N:1]=[CH:32]1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(N)c(N)c2)CC1
Reactant: CCOC(OCC)OCC
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc3[nH]cnc3c2)CC1
Temperature: 25 °C

Procedure:
2-(3,4-diaminophenyl)-N-(4-methyl-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylmethyl)-propionamide (48 mg, 0.110 mmol) was combined at RT with triethyl orthoformate (2 ml). The reaction mixture was heated to reflux for 2 h and cooled to RT. The reaction mixture was combined with water and repeatedly extracted with DCM. The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (DCM/MeOH=10:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:25])#[N:2].CI.[C:31]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:31])[S:13]([C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:25])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4ccccc4s3)C2=O)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN([C@H]1CCN(Cc2cccc(C#N)c2)C1=O)S(=O)(=O)c1cc2ccccc2s1
Reaction time: 6 h
Yield: 96.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [1-(3-cyano-benzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.25 g, 0.61 mmol) in 3 mL of DMF is added methyl iodide (0.13 g, 0.91 mmol) followed by K2CO3 (0.13 g, 0.91 mmol). The solution is stirred at ambient temperatures for 6 h. After this time, the solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The residue is triturated with Et2O to give the title compound (0.25 g, 0.59 mmol) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[CH:10]([C:19]([OH:21])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[CH:10]([C:19]([Cl:25])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Yield: 100 %

Procedure:
A solution of the product from step c) (4.6 g, 12.6 mmol) in CH2Cl2 (63 ml) was treated with DMF (3-5 drops) and oxalyl chloride (2.4 g, 18.9 mmol) for 2 hours. Next, the solvent was evaporated in vacuo to give 4.04 g (100%) of the subtitle compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(Cl)cc1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Cl)cc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.42 (s, 1H), 7.57 (dt, J=8.9, 2.3 Hz, 2H), 7.92 (dt, J=8.9, 2.3 Hz, 2H), 8.17 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H), 8.96 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+, 275 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]#[N:21])=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2c(Cc3nnn[nH]3)cnn2-c2ccccc2)cc1

Procedure:
A mixture of 29.4 g of (5-p-chlorophenyl-1-phenyl-pyrazol-4-yl)-acetonitrile, 8.06 g of sodium azide, 6.64 g of NH4Cl and 140 ml of dry DMF is heated at 120° for 17 hours, with stirring, and is then evaporated. After the customary working up, 5-p-chlorophenyl-1-phenyl-4-(tetrazol-5-ylmethyl)-pyrazole is obtained; m.p. 230°-232°.
Reaction SMILES: [Br-].[C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][CH2:10][CH2:11][N+:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[OH:22])[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].C(=O)(O)[O-].[Na+]>CO.[Pd]>[C:23]1([CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([OH:22])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1cccc2c[n+](CCCC(c3ccccc3)c3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: Oc1cccc2c1CCN(CCCC(c1ccccc1)c1ccccc1)C2
Yield: 100.9 %

Procedure:
To a solution of 2-(4,4-diphenylbutyl)-5-hydroxyisoquinolinium bromide (2.29 g, 5.27 mmol) in 100 mL of methanol was added 20% Pd/C catalyst (0.7 g). The reaction mixture was shaken under 50 psi of hydrogen at room temperature for 18 hours. The catalyst was then removed by filtration through a pad of Celite. The residue was washed with methanol, and the filtrate was concentrated under vacuum. The white solid obtained was neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2×200 mL). The organic extracts were collected and dried with magnesium sulphate, filtered and concentrated to give 1.9 g of crude product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: CCC(CC)OC(=O)Cl
Solvent: C1CCOC1
Product: CCC(CC)OC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added 3-pentyl chloroformate (147 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 17%-42%, 25 min) to give the title compound (230 mg, 43%) as TFA salt. 1H NMR: DMSO 400 MHz δ 9.97 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.35 (q, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (J=8.4 Hz, 1H), 6.47 (s, 1H), 6.35 (q, 1H), 4.88 (s, 2H), 4.50 (q, 3H), 1.50 (q, 4H), 0.84 (t, 6H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].Cl>[OH-].[Na+]>[CH2:1]([O:8][CH2:11][CH2:10][C:9]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
To a mixture of benzyl alcohol (108 g, 1 mol) and 40% aqueous solution of sodium hydroxide (10 mL) was added prop-2-enenitrile (58.3 g, 1.1 mol) and the mixture was stirred for 6 hours at room temperature. The mixture was neutralized with 1 N hydrochloric acid, and extracted with dichloromethane (300 mL). The organic layer was washed with 5% solution of sodium hydroxide (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo to afford 150 g of the desired compound (yield was 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[C:27]([CH3:34])([CH3:33])[CH2:26]2)=[CH:21][C:20]=1[O:35][CH3:36]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[C:27]([CH3:33])([CH3:34])[CH2:26]3)=[CH:21][C:20]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CNC1CCN(c2ccc(N)c(OC)c2)CC1(C)C
Product: CNC1CCN(c2ccc(Nc3ncc(Cl)c(-c4c[nH]c5ccccc45)n3)c(OC)c2)CC1(C)C

Procedure:
Starting materials: 3-(2,5-dichloropyrimidm-4-yl)-1H-indole (INTERMEDIATE 2) and), 1-(4-amino-3-methoxyphenyl)-N,3,3-trimethylpiperidin-4-amine (INTERMEDIATE 44).
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27].C(N(CC)CC)C>CC#N>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:29]([NH:28][CH2:26][CH3:27])=[S:30])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CCN=C=S
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (2.04 g, 5.19 mmol) in CH3CN (80 mL) was added ethyl isothiocyanate (1.36 g, 15.57 mmol), followed by triethylamine (0.94 g, 9.31 mmol). The reaction mixture was heated to reflux and stirred for 3 h. The organic layer was concentrated, and redissolved in CH2Cl2. The reaction was then washed with a minimal amount of saturated aqueous NaHCO3 solution. The aqueous layer was extracted an additional two times with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The desired (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-ethylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate was obtained as a yellow oil (2.21 g, 98% yield) following flash chromatography (EtOAc/hexanes, 1:1). 1H NMR (500 MHz, CDCl3) δ 1.19 (m, 3H), 1.81 (d, 1H, J=4.0 Hz), 2.05 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.14 (s, 3H), 3.40 (s, 1H), 3.85 (m, 1H), 4.12 (m, 1H), 4.28 (m, 1H), 4.81 (s, 1H), 5.19 (m, 1H), 5.73 (d, 1H, J=7.7 Hz), 6.00 (s, 1H), 6.12 (d, 1H, J=15.0 Hz); 13C NMR (125 MHz, CDCl3) δ 14.39, 20.81, 20.96, 21.07, 21.25, 57.84, 60.67, 61.95, 68.08, 72.99, 73.31, 93.12, 163.03, 169.60, 170.97, 171.88.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:20]=[C:19]2[NH2:34].C1(N=C=NC2CCCCC2)CCCCC1.C>CC(C)=O.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([NH2:34])=[N:20][C:21]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([CH:2]4[O:1][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3]4)=[O:13])[CH2:32][CH2:33]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(O)C1COc2ccccc2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 93.6 %

Procedure:
In a reaction vessel, 0.25 mol (45.0 g) of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid, tetrahydrofuran (328 ml) and 6,7-dimethoxy-2-(piperazin-1-yl)quinazolin-4-amine (0.22 mol; 63.58 g) were charged and contents were stirred at 20-25° C. for 5-10 min. To the resulting mixture dicyclohexylcarbodiimide (0.26 mol; 54.0 g) was added and stirring continued at 20-25° C. for 1.5 hr. To the resulting reaction mass charcoal was added and contents were stirred at 26-28° C. for 45 min. The contents were filtered through celite and washed with tetrahydrofuran. The solvent was distilled out at 35° C. under reduced pressure to obtain solid residue. Acetone (1000 ml) was added to the solid and contents were refluxed for 2 hr. On cooling to 25-28° C., the slurry was filtered, washed with acetone and dried at 60° C. under reduced pressure to obtain 93 g of doxazosin base (HPLC purity −99.0%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:31][CH:32]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 150 mg (0.3394 mmol) of benzyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate and 50 mg of 10% palladium on carbon in 5 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was then filtered and the filtrate was concentrated in-vacuo. The residue was dissolved in ether and extracted with aqueous NaOH solution. The aqueous extract was then acidified with glacial acetic acid and extracted with ether. The ether extract was washed with saturated NaCl solution and then concentrated in-vacuo. The resultant residue was recrystallized from ethyl acetate to give the title compound as a white solid. PMR (CDCl3): δ 1.34 (6H, s), 1.36 (6H, s), 1.76 (4H, s), 7.33 (2H, d, J~8.6 Hz), 7.46 (1H, d, J~7.8 Hz), 7.94 (1H, dd, J~7.8 Hz, 1.8 Hz), 8.16 (1H, d, J~1.8 Hz), 8.21 (2H, d, J~8.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)#[CH:22]>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:22]#[C:21][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1Br
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from tert-butyl[2-bromo-4-(trifluoromethyl)phenoxy]acetate (Intermediate 35) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc