Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=2)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:20]2[C:21](=[O:39])[N:22]([C:27]3[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:17][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-n2cc(Br)nc(Br)c2=O)c(C)cc1F
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c(C)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 111.8 %

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (1.026 g) in dioxane (10 mL) was treated with methyl 5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate (Example 318d, 1.500 g) and Hunig's Base (0.936 mL) under nitrogen. The resulting solution was stirred at 100° C. for 16 h. The cooled mixture was diluted with 2 M HCl and extracted with diethyl ether. The combined organics were dried (MgSO4) and evaporated to afford the subtitle compound (2.310 g) as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]=[N+:11]=[N-:12])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 4-bromobenzyl bromide (54) and sodium azide (2.0 equiv.) in DMF was stirred at 50° C. for 3 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to yield 55 as colorless oil in 92% yield.
Reaction SMILES: CC1C=CC(C(O[C@@H]([C@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:42][CH2:41]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[CH:35]2[CH2:66][C:67]([O:69]C)=[O:68].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:41][CH2:42][N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH3:53])[CH:47]=3)[CH2:44][CH2:45]1)[N:36]([C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[CH:56][C:55]=1[O:64][CH3:65])[C@H:35]2[CH2:66][C:67]([OH:69])=[O:68]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
(2S,3S)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid-methyl {8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (10.1 g, containing 14 ppm of Pd) are suspended in ethyl acetate (100 ml) and shaken with saturated aqueous sodium bicarbonate solution (100 ml) until both phases are clear. The phases are separated and the organic phase is concentrated in a rotary evaporator. The residue is dissolved in 1,4-dioxane (100 ml) and 1N sodium hydroxide solution (31.2 ml) and stirred at room temperature for 3 h. Subsequently, the pH is adjusted to 7.5 using 1N hydrochloric acid (ca. 17 ml), MIBK (80 ml) is added, then the pH is readjusted to 7.0 using 1N hydrochloric acid (ca. 2 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (40 ml) and concentrated, then dissolved in ethanol (40 ml) again and concentrated and dried at 50° C. in a high vacuum. The solidified foam is dried at 45° C. for 18 h in the VDO using entraining nitrogen. A total of 5.05 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are obtained as an amorphous solid, corresponding to 85.0% of theory.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][CH3:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.770 ml, 7.86 mmol) is added to (R)-[3-(7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.400 g, 1.05 mmol) and triethylamine (0.726 ml, 5.24 mmol) in dichloromethane (5 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a dark yellow solid. HPLC r.t. 5.28 min; MS for C20H26FN3O5 m/z 408.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:19])[NH:10]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[ClH:26].Cl.C(O)C>CO>[ClH:26].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:20][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:19])[CH2:8][CH2:7]2)[C:17]#[CH:18]
Reactant: C#CCOc1ccc(OCC2CO2)c2c1NC(=O)CC2
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C#CCOc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Reaction time: 12 h

Procedure:
2 g of 5-(2,3-epoxypropoxy)-8-(2-propynyloxy)-3,4-dihydrocarbostyril was dissolved in 15 ml of methanol, and 2.6 g of t-butylamine was added to the solution, followed by allowing the mixture to stand at 15°-20° C. for 12 hours. After completion of the reaction, the methanol and the t-butylamine were evaporated under reduced pressure, and the resulting crude oil was converted into the hydrochloride thereof using hydrochloric acid and ethanol. The solvent was evaporated under reduced pressure, and the resulting crystals were dissolved in water and washed with chloroform to remove impurities. The aqueous layer was made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to obtain colorless crystals, which were converted into the hydrochloride thereof with hydrochloric acid-ethanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from isopropanol to obtain 1.6 g of 8-(2-propynyloxy)-5-[3-(t-butylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril hydrochloride having a melting point of 182°-183° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br.ClCCl>C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° ) solution of 4-trifluoromethoxyphenol (35.6 g, 0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for 1 h. and at room temperature for 2 h. Dichloromethane (200 ml) and waster (400 ml) ware added and the organic phase was washed further with water (400 ml), brine (200 ml) and dried (MgSO4). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250 MHz, CDCl3) δ7.38 (1H, d, J 2.1 Hz), 7.13 (1H, dd, J 9.1, 2.1 Hz), 7.03 (1H, d, J 9.1 Hz), and 5.53 (1H, s).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:1](=[O:3])[CH3:2])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CNCc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (6 μL) was added to a solution of the product from step (i) (23 mg) and triethyl amine (9 μL) in THF (1 mL), and the mixture was stirred at RT for 3 h. The mixture was quenched with water, extracted with EtOAc, combined organic layer was washed with brine, dried and concentrated under reduced pressure. The sub-title compound (25 mg) was obtained as a colourless gum, which was used for next reaction without further purification; LC-MS: m/z=585.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[CH:25]([C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)=O>C(O)C>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:2]#[C:25][C:27]3[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(/C=C/C(=O)O)cc3)ccc21
Yield: 39.3 %

Procedure:
Using a procedure similar to that described in Example 6b, 16.5 g (44 millimoles) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)methylphosphonate (about 85% strength), 7.8 g (44 millimoles) of 4-formylcinnamic acid and 15.5 g (137 millimoles) of potassium tert.-butylate were converted to 6.2 g (39%) of the title compound of melting point 256°-258° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=3)=[C:15]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)[S:14][C:13]=2[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([CH2:17][C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:41][C:13]=3[S:14][C:15]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: ClCCN1CCCC1
Reactant: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Agent: Cl
Product: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1OCCN1CCCC1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 6-benzyloxy-3-[(3-methoxy-4-hydroxyphenyl)methyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part E) and 1-(2-chloroethyl)pyrrolidine hydrochloride by a method similar to that outlined in Example 188, Part A.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C@H:15]2[CH2:20][CH2:19][C@H:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][CH:7]=1)(=[O:5])=[O:4].[C:28](NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.S(Cl)(Cl)(=O)=O>>[CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C@H:15]2[CH2:20][CH2:19][C@H:18]([CH3:21])[CH2:17][CH2:16]2)=[O:13])=[N:8][C:7]=1[CH3:28])(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: O=S(=O)(Cl)Cl
Product: CNS(=O)(=O)c1sc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)nc1C

Procedure:
The title compound was prepared in a similar manner to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonic acid methylamide using 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride as the sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:18]([I:19])=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]\N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>CCO>[NH2:23][C:22]1[N:24]=[CH:12][C:7]2[CH2:8][C:9](=[O:11])[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([I:19])=[CH:17][C:5]=3[C:6]=2[N:21]=1
Reactant: CN(C)/C=C1/CC(=O)Nc2cc(Cl)c(I)cc2C1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
A suspension of (4Z)-8-chloro-4-[(dimethylamino)methylene]-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (9.50 g, 24.3 mmol), guanidine hydrochloride (2.56 g, 26.8 mmol), and potassium carbonate (11.1 g, 80.3 mmol) in EtOH (143) was allowed to stir while heating at 70° C. in a sealed reaction vessel. After 19 h, the reaction mixture was allowed to cool to room temperature then added to water (200 mL) and allowed to stir for 1 h. The resulting tan solid was collected via suction filtration, washed with water, and dried in a vacuum oven to give 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (7.69 g, 82%). LCMS (FA): m/z=387 (M+H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][O:27]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1.[Cu](I)I>[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:27])[CH2:28][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:12])([F:11])[F:10])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCOC(C3(c4ccccc4)CO3)C2)cc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: I[Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC(Cc1ccccc1C(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: -78 °C
Yield: 11.8 %

Procedure:
To a suspension of magnesium turnings in tetrahydrofuran (2 mL) at room temperature under nitrogen atmosphere was added a solution of 1-bromo-2-trifluoromethyl-benzene (7.6 g, 5 equiv., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to −78° C. and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4-Benzyl-2-(2-phenyl-oxiranyl)-morpholine (2 g, 1 equiv.) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MgSO4, and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12%). LCMS (6 minutes method) [M+H]+=442 @ Rt 3.05 min. major peak.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH2:13][CH2:14]Br>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. 1,2-Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:35])([F:34])[C:18]([C:20]1[S:24][C:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])=[CH:22][CH:21]=1)=[O:19]>C(O)=O>[CH3:1][CH:2]1[N:7]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:23]3[S:24][C:20]([C:18](=[O:19])[C:17]([F:16])([F:34])[F:35])=[CH:21][CH:22]=3)[CH:26]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Solvent: O=CO
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 39 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described for example 37 step 3 (95 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.42 (d, J=1.9 Hz, 1H), 7.97-7.96 (m, 1H), 7.80-7.77 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.75-7.74 (t, J=1.5 Hz, 1H), 7.68-7.65 (dd, J=9.1 Hz, 2.4 Hz, 1H), 7.58-7.54 (t, J=7.6 Hz, 1H), 7.48-7.45 (m, 2H), 6.64-6.62 (d, J=9.1 Hz, 1H), 4.40-4.23 (m, 4H), 3.42-3.37 (m, 2H), 3.16-3.09 (m, 1H), 1.33-1.31 (m, 3H). MS (ESI) m/z: Calculated for C24H19F3N4O2S: 484.12. found: 529.7 (M+HCOOH)−
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][N:6]2[CH:10]=[CH:9][N:8]=[N:7]2)[N:13]=[N:12]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCn1ccnn1
Product: CC(=Cc1ccccc1)Cn1cc(CCCn2ccnn2)nn1
Yield: 99.6 %

Procedure:
1-Pent-4-ynyl-1H-[1,2,3]triazole (0.100 g, 0.739 mmol) was reacted with (3-Azido-2-methylpropenyl)-benzene (0.154 g, 0.889 mmol) following the general procedure for click reactions outlined above to produce 1-(2-Methyl-3-phenyl-allyl)-4-(3-[1,2,3]triazol-1-yl-propyl)-1H-[1,2,3]triazole (0.227 g, Quantitative) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.77 (s, 2H), δ 7.40-7.25 (m, 5H), δ 6.47 (s, 1H), δ 5.05 (s, 2H), δ 4.48 (t, 2H), δ 2.62 (t, 2H), δ 2.50 (t, 2H), δ 2.21 (m, 2H), δ 1.74 (s, 3H) ppm; 13C (75 MHz, DMSO) δ 146.4, 137.1, 134.8, 133.6, 132.8, 129.4, 129.3, 129.2, 128.9, 127.6, 123.0, 57.9, 54.0, 32.9, 29.6, 22.7, 16.2 ppm; HRMS (ESI) calcd for C17H21N6 (M+) 309.1822. found 309.1821.
Reaction SMILES: N1C=CC=C(CN)C=1.[S:9]1[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10]1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][N:46]2[CH2:50][C@@H:49]([CH3:51])[N:48]([C:52]3[S:53][C:54]([C:58](O)=[O:59])=[C:55]([CH3:57])[N:56]=3)[C:47]2=[O:61])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][N:46]2[CH2:50][C@@H:49]([CH3:51])[N:48]([C:52]3[S:53][C:54]([C:58]([NH:15][CH2:14][C:13]4[S:9][CH:10]=[N:11][CH:12]=4)=[O:59])=[C:55]([CH3:57])[N:56]=3)[C:47]2=[O:61])=[CH:43][CH:42]=1
Reactant: NCc1cncs1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)NCc1cncs1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with thiazol-5-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (67%): mp 70-73° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.62 (t, J=5.4 Hz, 1H), 7.76 (s, 1H), 7.33-7.28 (m, 2H), 7.18-7.13 (m, 2H), 4.56-4.39 (m, 5H), 3.59-3.56 (m, 1H), 3.00 (dd, J=9.0, 2.7 Hz, 1H), 2.45 (s, 3H), 1.35 (d, J=6.0 Hz, 3H); MS (ES+) m/z 445.7 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12](OC)=[O:13])(=[O:9])=[O:8].[CH3:24][CH:25]([CH3:27])[O-:26].[Na+].C(O)(=O)C>C(O)(C)C>[ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:26][CH:25]([CH3:27])[CH3:24])=[O:13])(=[O:9])=[O:8]
Reactant: CC(C)[O-]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)OC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN(C)C
Yield: 31 %

Procedure:
A solution of methyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoate hydrochloride (12.0 g, 32.6 mmol) in dry isopropanol (500 mL) containing sodium isopropoxide (39 mmol) was stirred at reflux under N2 for 18 hours. After adding glacial acetic acid (1 mL) and concentrating under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The residue was converted to the hydrochloride salt with ethanolic anhydrous hydrogen chloride and recrystallized from methanol - ethyl acetate to give 4.0 g (31%) of product, m.p. 187.0-190.0° dec. Anal Calc'd for C14H21N3O6S.HCl: C, 42.47; H, 5.60; N, 10.61
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2>CO.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([OH:17])[CH2:12][CH2:11]2
Reactant: O=C1CCc2cc(-c3cccs3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1CCc2cc(-c3cccs3)ccc21
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a slurry of sodium borohydride (0.22 g, 5.86 mmol) in methanol (6mL) at 0° C. was added a solution of 5-(2-thienyl)-2,3-dihydro-1H-inden-1-one (0.50 g, 2.34 mmol ) in methanol (2 mL). The reaction was slowly warmed to room temperature and stirred until the reaction was completed as monitored by thin layer chromatography (4 h). The reaction mixture was carefully quenched with 1.0 N aqueous hydrochloric acid at 0° C. until a clear solution was obtained. Diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride (brine), and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography on silica (7:3 hexanes/ethyl acetate) gave 5-(2-thienyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 59% yield) as solid. 1H NMR (400 MHz, CDCl3): 7.48 (m, 2H), 7.38 (br d, 1H), 7.26 (m, 2H), 7.08 (dd, 1H), 5.21 (t, 1H), 3.04 (m, 1H), 2.80 (m, 1H), 2.50 (m, 1H), 2.10 (brs, 1H), 1.93 (m, 1H).