Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C:33]([CH:36]2[O:40][CH2:39][CH2:38][O:37]2)=[CH:34][CH:35]=1)CCC>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[O:32][C:33]([CH:36]5[O:40][CH2:39][CH2:38][O:37]5)=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Yield: 68.1 %

Procedure:
(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis(triphenylphosphine) palladium (0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δH [2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:49][CH2:48][C:47]([O:46][CH3:45])=[O:50])=[O:19])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCOCC1)C(=O)O
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A 100-mL round-bottomed flask was charged with N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanine (3.11 g, 11.38 mmol), HATU (5.41 g, 14.22 mmol), glycine methyl ester hydrochloride (1.714 g, 13.65 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10 mL of DMF. To this was added Hünig's base (4.37 mL, 25.03 mmol). After 30 min at room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The layers were separated and the organic extracts were washed with water (2×100 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated to give methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[O:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(F)c2)CC(C)(C)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (137) (0.30 g, 0.68 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 138 was obtained as an off-white solid (0.227 g, 81%). mp 125-128° C. 1H NMR (400 MHz, DMSO-d6): δ1.10 (s, 6H), 1.12 (s, 6H), 2.10 (s, 2H), 2.14 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.75-6.80 (m, 1H), 6.82-6.95 (m, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 9.80 (s, 1H), 12.36 (s, 1H). LCMS (ES): m/z 409 (M−H)−. Anal. Calcd for C25H27FO4.0.4H2O: C, 71.89; H, 6.71; Found: C, 71.88; H, 6.92.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[C:12](=[O:20])[CH:13]=[C:14]([CH:17]([F:19])[F:18])O[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl>CO.CCOCC>[CH2:3]([O:10][C:11]1[C:12](=[O:20])[CH:13]=[C:14]([CH:17]([F:19])[F:18])[N:2]([CH3:1])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A 2.0M methylamine solution in methanol (19.0 mL, 38.0 mmol) was added to a suspension of 5-benzyloxy-2-difluoromethyl-pyran-4-one (3.15 g, 12.5 mmol) in methanol (18 mL). The reaction mixture slowly turned into a clear yellow solution. The progress of the reaction was monitored by TLC using a mixture of methanol and dichloromethane (1/20, v/v) as eluant, and HPLC method 1 as described above. After 70 minutes, the reaction mixture was concentrated in vacuo to obtain an oil. The oil was diluted with ether and allowed to stir overnight at room temperature. A precipitate had formed and it was collected by filtration. The solid was washed with ether, and the title compound was obtained as an off white solid (2.50 g, 75% yield). The purity of this material was analysed by HPLC Method 1 (peak area percent is 98.8% at λ=288 nm) as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.75 (s, 1H), 7.44-7.34 (m, 5H, ArH), 7.12 (t, J=53.0 Hz, 1H, CF2H), 6.48 (s, 1H), 5.02 (s, 2H, OCH2), 3.71 (s, 3H, N—CH3).
Reaction SMILES: [OH:1][C:2]1[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1C(OCC)=O.C(O)C.O.C(=O)=O.[Cl-].[Na+]>C(OCC)(=O)C>[CH3:9][CH:8]([CH3:10])[CH2:7][C@@H:6]1[NH:5][C:4](=[O:11])[CH2:3][C:2]1=[O:1]
Reactant: CCOC(=O)C1=C(O)[C@H](CC(C)C)NC1=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C[C@@H]1NC(=O)CC1=O
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
Approximately 150 mmol of (S)-2,5-dihydro-4-hydroxy-5-(2-methylpropyl)-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester is added as rapidly as possible to 1 L of boiling ethanol-water (1:1, pot temperature 85-87° C.) in a 3 L beaker with vigorous stirring. Complete solution occurs rapidly and vigorous effervescence is observed. Refluxing is continued 20 minutes until the CO2 evolution ceases. The beaker is plunged into an ice bath to rapidly cool the solution, 120 g of sodium chloride and 500 ml of ethyl acetate are added and the organic layer is separated. The aqueous layer is extracted with 2×500 ml of ethyl acetate and the organic fractions combined, dried over magnesium sulfate and evaporated to a solid. The solid is slurried in 200 ml of diethyl ether, diluted with 200 ml of ethyl acetate, and stirred approximately 15 minutes until most of the solid dissolves. The insoluble material is filtered off and the filtrate evaporated to afford 15.9 g of (S)-5-(2-methylpropyl)-2,4-pyrrolidinedione as an off-white solid; mp 94°-95° C. [α]D23 =-80° (C=1%, chloroform). TLC (ethyl acetate, silica gel, ultra violet (uv)) Rf =0.4.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[C:44]([C@@H:45]4[CH2:47][C@H:46]4[CH2:48][O:49][CH3:50])=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([F:51])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>>[C:24]12([CH2:34][O:35][C:36]3[C:44]([C@@H:45]4[CH2:47][C@H:46]4[CH2:48][O:49][CH3:50])=[CH:43][C:39]([C:40]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:41])=[C:38]([F:51])[CH:37]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: COC[C@@H]1C[C@H]1c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CS(N)(=O)=O
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COC[C@@H]1C[C@H]1c1cc(C(=O)NS(C)(=O)=O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)cyclopropyl)benzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.0678 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 11.89 (br s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 3.66 (d, J=9.4 Hz, 1H), 3.61 (d, J=9.5 Hz, 1H), 3.46-3.35 (m, 2H), 3.34 (s, 3H), 3.25 (s, 3H), 2.04-1.89 (m, 4H), 1.78-1.61 (m, 12H), 1.34-1.22 (m, 1H), 1.06-0.97 (m, 1H), 0.90-0.81 (m, 1H); MS (ES−) m/z 464.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=O.[Cl-].[OH:31][NH3+:32].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[N:32][OH:31]
Reactant: [NH3+]O
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
27 g (65.1 mmol) of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.5 g (65.1 mmol) of hydroxylammonium chloride and 12.9 g (163 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 13.5 g of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone oxime as a beige solid with a melting point of 76-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.88 (t, 3H), 1.20-1.40 (m, 24H), 1.40-1.50 (m, 2H), 1.75-1.84 (m, 2H), 3.96-4.02 (m, 2H), 6.89(E)/6.95(Z) (d, 2H), 7.43(E)/7.52(Z) (d, 2H), 8.28(Z)/8.43(E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=7:3.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>O>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)cc1

Procedure:
A suspension of 8.5 g. (0.0284 mole) of ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 29 ml. of 1N sodium hydroxide solution is heated under reflux for 20 minutes. The yellow solution is diluted with water and added to dilute hydrochloric acid. The precipitated solid is collected, dried in vacuo, and recrystallized from 2-propanol to give 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid, m.p. 160-161° C. Anal. Calcd. for C16H17NO3: C, 70.83; H, 6.32; N, 5.16%. Found: C, 70.90; H, 6.39; N, 5.25%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH2:10]([C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH:17]=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
(S)—N-Bocphenylalaninol (5 g, 0.019 mol) was dissolved in dichloromethane (150 mL) and triethylamine (8.3 mL, 3 equivalents) at 0° C. and treated with a solution of pyridine-sulfur trioxide complex (9.5 g, 3 equivalents) in DMSO (30 mL) over several minutes. After 1 h at 0° C., the mixture was added to ice water (200 mL). The dichloromethane was evaporated and the mixture was extracted with ether (100 mL, 4×). The organic layer was washed with 10% citric acid, water, saturated sodium bicarbonate, brine, dried over sodium sulfate, and the solvents were evaporated to give 5.3 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccn2)cc1

Procedure:
By following a procedure analogous to Example 27 starting from the 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 25 and 4-methoxyphenylboronic acid, 2-(4-methoxyphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige solid (yield=53%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1N.N([O-])=O.[Na+].[S:17](=[O:19])=[O:18].[ClH:20]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: Nc1c(F)cccc1C(F)(F)F
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1c(F)cccc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a mechanically stirred mixture of 2-fluoro-6-trifluoromethylaniline (10.0 g, 55.8 mmol) in concentrated hydrochloric acid (20 mL) and glacial acetic acid (6 mL) was added a solution of sodium nitrite (4.25 g, 61.4 mmol) in water (6 mL) dropwise at −10° C. The resulting orange/white suspension was stirred at −10° C. for 30 minutes, then added in portions to a solution of cuprous chloride (1.7 g, 16.7 mmol) and sulfur dioxide (about 20 g, 312 mmol) in glacial acetic acid (60 mL) at 0° C. A mild exotherm and vigorous gas evolution were observed after each addition. The resulting dark green mixture was warmed to room temperature and stirred for 25 minutes (min). The reaction was poured into ice water (600 mL) and extracted with diethyl ether. The organics were combined, washed with aqueous sodium bicarbonate, dried (MgSO4), filtered, and the solvent removed in vacuo to afford the crude product as a dark oil (8.45 g, 15 58% yield).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][C:8]([CH2:11]O)=[CH:9][CH:10]=1)[CH3:4].Cl.[NH2:14][CH2:15][CH2:16][SH:17].O.[OH-].[Na+]>Cl.CCOCC.C(O)C>[ClH:1].[ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:7][C:8]([CH2:11][S:17][CH2:16][CH2:15][NH2:14])=[CH:9][CH:10]=1)[CH3:4]
Reactant: CN(C)Cc1ccc(CO)s1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCN)s1
Reaction time: 8 h
Yield: 144.5 %

Procedure:
A solution of 2-(dimethylaminomethyl)-5-(hydroxymethyl)thiophene hydrochloride (8.0 g) in concentrated hydrochloric acid (50 ml) was added dropwise to a stirred solution of cysteamine hydrochloride (4.37 g) in concentrated hydrochloric acid (50 ml) cooled in an ice-bath. The temperature of the mixture was maintained below 5° during the addition. The mixture was allowed to reach room temperature and was stirred overnight and poured into water. The aqueous mixture was adjusted to pH 12 with 2 N sodium hydroxide and was extracted with ethyl acetate (750 ml). The extract was dried and evaporated to give an oil which was dissolved in dry ether and hydrogen chloride in ethanol was added and the solid was filtered off to give 2-[5-dimethylaminomethyl-2-thienylmethylthio]ethylamine dihydrochloride (8.44 g) m.p. 190°-194°.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][NH:12][C:13]([C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C@@H:22]2[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]2[C:28](=[O:49])[CH2:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:50][CH2:51]C1CC1>>[Br-:50].[CH2:1]([N+:5]1([CH3:51])[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][NH:12][C:13]([C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C@@H:22]2[CH2:26][C@@H:25]([OH:27])[CH2:24][N:23]2[C:28](=[O:49])[CH2:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])=[O:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: BrCC1CC1
Product: CCCC[N+]1(C)CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [Br-]

Procedure:
The title compound was prepared by a method similar to Example 128, using (2R)-N-{((3R)-1-butyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide and (bromomethyl)cyclopropane. The compound was obtained as a white foamy substance.
Reaction SMILES: [H][H].[Br:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pt]>[Br:3][C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1Br
Yield: 98.9 %

Procedure:
Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm−1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[S:12](=O)[CH:13]=[CH:14][C:10]=3[CH2:9][N:8]([CH3:16])[CH2:7][C:6]=12.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(NCC)C.CN(C)C=O.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.[Cu]I>[CH3:16][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[N:5]2[CH:4]=[N:3][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]2[CH2:7]1
Reactant: CN1CC2=C(n3cnc(I)c3C1)S(=O)C=C2
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN1Cc2ccsc2-n2cnc(C#Cc3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of 5,6-dihydro-7-iodo-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one (prepared in accordance with Example 73) was dissolved in 47 ml of diethylamine and 20 ml of dimethylformamide. 1.75 ml of phenylacetylene, 105 mg of bis-(triphenylphosphine)-palladium(II) chloride and 17 mg of copper(I) iodide were then added. The mixture was stirred at room temperature for 2 hours and then concentrated in a vacuum. The residue was diluted with 200 ml of dichloromethane and washed twice with water. The aqueous washings were extracted twice with dichloromethane. The combined dichloromethane solutions were dried over sodium sulphate and chromatographed through 300 g of silica gel. Elution was carried out first with trichloromethane and trichloromethane/ethanol mixtures 199:1 and 99:1. There was then eluted with a trichloromethane/ethanol mixture 97:3 an oily substance which can be crystallized from isopropanol/water. After repeated recrystallizations from isopropanol/water there was obtained 5,6-dihydro-5-methyl-7-(phenylethynyl)-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine one of melting point 143°-144°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Reactant: CNc1ccc(OC(C)C)cc1
Product: Cc1nc(N(C)c2ccc(OC(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The title compound was synthesized from 4-chloro-2-methyl-6-nitro-quinazoline and (4-isopropoxy-phenyl)-methyl-amine by a procedure similar to Example 1b. 1H NMR (DMSO-d6) δ 8.5-7.1 (7H), 4.73 (m, 1H), 3.7 (s, 3H), 2.7 (s, 3H), 1.32 (d, 6H); LC-MS (ESI+; 353 ([M+H]+)).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[OH-].[K+].C1(=O)O[CH2:27][CH2:26][O:25]1.C(=O)=O>CN(C)C=O>[OH:25][CH2:26][CH2:27][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: O=C1OCCO1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)nn(CCO)c1=O
Temperature: 100 °C

Procedure:
17.7 grams (0.065 mole) of the product of Example 1 was dissolved in 60 mls of dry dimethylformamide along with 0.25 grams of potassium hydroxide and 7.5 grams (0.085 mole) of ethylene carbonate. The mixture was heated to 100° C. and maintained for 2 hours until no carbon dioxide was liberated. The solution was then heated at 110° C. for 30 minutes. The solution was filtered and the dimethylformamide was distilled under reduced pressure with a mechanical pump. The solid was dried in a drying pistol using xylene as the solvent. The residual solid was recrystallized from ethyl alcohol to give 10.4 grams (50%) yield of a solid melting at 197°-198° C. Calculated for C19H15N3O2, C, 71.9; H, 4.8; N, 13.2. Found: C, 71.7; H, 4.71; N, 13.5. The infrared spectra showed the OH group at 2.9μ, the nitrile band at 4.5μ, and the carbonyl band at 6.0μ. The NMR confirmed that the product was the desired material.