Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[C:13]([CH:16]=1)[C:14]#[N:15]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: OCC1CC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCC1CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sodium hydride, 60% suspension in oil (3.6 g, 0.09 mol), is added to a solution of cyclopropylmethanol (6.49 g, 0.09 mol) in dry DMF (200 ml) at 0° C. under nitrogen. After 30 min at 0° C., 5-bromo-2-fluorobenzonitrile (12.0 g, 0.06 mol) in dry DMF (50 ml) is added, and the reaction is stirred at 50° C. for 16 h. Ice-water (200 ml) is added to the reaction mixture, which is then extracted with ethyl acetate (2×200 ml). The organic phases are washed with water (2×200 ml) and saturated sodium chloride solution (1×200 ml) and dried over sodium sulfate. After removal of the solvent, the crude product is purified by chromatography, giving 14 g of a yellow oil;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[Cl:20])[CH3:11])[NH2:5].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:8]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])=[CH:7][C:6]2[S:21][C:22]([NH2:23])=[N:5][C:4]=2[CH:3]=1
Reactant: N#C[S-]
Reactant: CC(Oc1ccc(N)cc1Cl)c1c(Cl)ccc(F)c1Cl
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1Cl)c1c(Cl)ccc(F)c1Cl
Yield: 61 %

Procedure:
5-Chloro-6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 1.19 g of 3-chloro-4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]aniline, 1.38 g of potassium thiocyanate and 0.182 cm3 of dibromine. We obtain 0.85 g of 5-chloro-6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of a yellow-coloured solid, which has the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1.[ClH:39]>C(O)C>[ClH:39].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[C:4]([CH3:38])[N:3]=1
Reactant: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(C)n1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc([C@H](O)CO)ns2)c(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of (S)—N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.70 g, 1.3 mmol) in ethanol (20 mL) was added concentrated HCl (2.4 ml) and the reaction was heated to 80° C. for 2 hours. The reaction was concentrated and the material triturated with EtOH. The solid was further purified by reverse phase HPLC to yield pure product. The product was taken up in ethanol and HCl (2M in ether) was added. The mixture was stirred for 2 hours and concentrated in vacuo and dried in vacuo to yield the product as the HCl salt (73.2 mg, 12%). Mass Spectrum (apci) m/z=469.2 (M+H−HCl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.[C:13]1([CH2:19][CH:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]([OH:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: O=CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc(C(O)Cc2ccccc2)cc1

Procedure:
A mixture of Mg turnings 2.4 g (0.1 mol) and 2 mL 1-bromo-4-(dimethoxymethyl)benzene (0.012 mol) in THF (100 mL) was heated under nitrogen atmosphere until the reaction starts. Subsequently additional 1-bromo-4-(dimethoxymethyl)benzene 14.71 mL (0.088 mol) dissolved in 30 mL THF was added slowly and the reaction refluxed for 1 h mixture to complete formation of the Gringnard reagent. A solution of 11.70 mL phenylacetaldehyde (0.1 mol) in 100 mL THF was added at to 0° C. and the reaction refluxed for 2 h upon completion of the addition. The mixture was worked up by pouring into saturated aqueous NH4Cl and extraction with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvents were evaporated under reduced pressure. The brown-black oily product was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16](OCC)=[O:17].[Li+].[BH4-].Cl>C1COCC1>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]
Reactant: CCOC(=O)c1cccc2c(Cl)c3ccccc3cc12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2c(Cl)c3ccccc3cc12
Temperature: 0 °C
Yield: 81.6 %

Procedure:
A solution of ethyl 10-chloroanthracene-1-carboxylate (37B, 14.86 g, 0.052 mol) in THF (300 mL) was treated with LiBH4 (Alfa, 1.14 g, 0.052 mol) and refluxed for 16 h. The reaction mixture was poured into ice water and acidified with conc. HCl to pH=2. The solid was filtered, washed with H2O (500 mL), air dried and then chromatographed on a plug of SiO2 (500 g) using EtOAc as the eluting solvent. The solvent was removed by rotary evaporation to give a solid, which was crystallized from CCl4 to give 10.3 g (81%) of 10-chloro-1-anthracenemethanol mp 138°-140°, (C, H, Cl).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH2:43]([O:49][C:50](Cl)=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:50]([O:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:51])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CCCCCCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: CCCCCCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-59 (0.487 g) as a colorless solid. 1H-NMR (300 MHz, CDCl3) δ 7.14 (2H, m), 7.07 (1H, d), 6.95 (1H, m), 6.62 (1H, dd), 6.54 (1H, d), 4.38 (2H, t), 3.95 (2H, t), 3.06 (4H, m), 2.89 (2H, t), 2.66 (6H, m), 2.47 (2H, t), 1.90-1.65 (6H, m), 1.49-1.30 (6H, m), 0.88 (3H, t). [M+H]+=576.2.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[OH:17]O>C(O)(=O)C>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:17]
Reactant: OO
Reactant: CC(C)CCSC1=C(O)CC(C)(C)CC1=O
Solvent: CC(=O)O
Product: CC(C)CCS(=O)C1=C(O)CC(C)(C)CC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3-hydroxy-2-isopentylthio-5,5-dimethyl-2-cyclohexen-1-one (10 g., 0.041 mole), 30 percent hydrogen peroxide (4.7 g., 0.041 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The mixture was poured into ice water and the precipitated pink crystals were filtered and dried (9.1 g., m.p. 64.5°-66°C.).
Reaction SMILES: [CH3:1][N:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[CH3:1][N:2]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCCC12CCN(c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCCCC12CCN(c1ccc(N)cc1)CC2
Reaction time: 5 h
Yield: 98.4 %

Procedure:
To a mixture of 1-methyl-9-(4-nitrophenyl)-1,9-diazaspiro[5.5]undecane (680 mg), ethanol (10 mL), and tetrahydrofuran (10 mL) was added 10% palladium-supported carbon (50% wet product) (150 mg), followed by stirring for 5 hours under a hydrogen gas atmosphere (1 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 4-(1-methyl-1,9-diazaspiro[5.5]undec-9-yl)aniline (0.6 g) as a pale purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: COC(=O)C=Cc1cc(OC)ccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(OC)ccn1

Procedure:
43.1 g of methyl 3-(4-methoxypyridin-2-yl)acrylate (starting material D1) in 600 ml of methanol are hydrogenated over 3.0 g of Pd/C (10% strength) until the starting material has disappeared (TLC). The catalyst is filtered off, and the mixture is then concentrated and dried under high vacuum. This gives 41.95 g of the title compound as a light-yellow oil. The mass spectrum shows the molecular peak MH+ at 196 Da.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[N:22][N:21]=[N:20]2)=[CH:15][C:14]=1[C:28]1[CH2:29][O:30][C:31]2([CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH:32]=1>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH2:36][CH2:37][C:31]2([O:30][CH2:29][C:28]([C:14]3[CH:15]=[C:16]([N:19]4[C:23]([C:24]([F:25])([F:26])[F:27])=[N:22][N:21]=[N:20]4)[CH:17]=[CH:18][C:13]=3[O:12][CH3:11])=[CH:32]2)[CH2:33]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C1=CC2(CCCNC2)OC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C1=CC2(CCCN(C(=O)c3ccccc3)C2)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
Benzoyl chloride (0.10 ml, 0.86 mmol) was added to a solution of 3-(2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]dec-3-ene hydrochloride (Desc. 11; 0.33 g, 0.79 mmol) in pyridine (5 ml) at 0° C. The mixture was stirred at 0° C. for 11/2 hours, allowed to warm to room temperature and concentrated in vacuo. 1M Hydrochloric acid (50 ml) was added to the residue and the mixture extracted with dichloromethane (2×25 ml). The combined extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography, eluting with 21/2% methanol in dichloromethane, to afford the title compound as a white foam (0.26 g, 68%), which was recrystallised from ethyl acetate/hexane, m.p. 154°-156° C.; (Found: C, 59.29; H, 4.45; N, 14.15, C24H33F3N5O3 requires C, 59.38; H, 4.57; N, 14.43%); δH (360MHz, DMSO-d6, 353K) 1.62 (1H, m), 1.75-1.85 (3H, m), 3.19 (1H, m), 3.39 (1H, br d, J 12Hz), 3.49 (1H, m), 3.80 (1H, m), 3.94 (3H, s, ArOCH3), 4.74 (1H, m, 2-CHaHB), 4.89 (1H, dd, J 12.6, 1.9Hz, 2--CHAHB), 6.52 (1H, br s, 4--CH=), 7.30 (1H, d, J 8.8Hz, 3'-H), 7.37 (5H, m, PhH), 7.55 (1H, d, J 2.6Hz, 6'-H), 7.63 (1H, dd, J 8.8, 2.6Hz, 4'-H); m/z (ES+) 486 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:6]1([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[C:2]2[C:3](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3Br)nc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc43)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-(2-bromophenethylamino)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.24 mmol, 1.00 equiv), Pd2(dba)3 (22 mg, 0.02 mmol, 0.10 equiv), BINAP (59.37 mg, 0.10 mmol, 0.40 equiv), Cs2CO3 (233 mg, 0.71 mmol, 3.00 equiv), 1,4-dioxane (5 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting solids were filtered out. The filtrate was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 90 mg (99%) of methyl 3-(indolin-1-yl)-2-phenylquinoxaline-6-carboxylate as a orange solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([O:35][C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:26])[CH:34]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(Oc5ccc(C#N)c(Cl)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 17 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 2-chloro-4-hydroxybenzonitrile (Aldrich, Cat. No. 346071). LCMS (M+H)+: m/z=476.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[N:20]([C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26])=[C:21]=[O:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:22]=[C:21]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:20]1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
A 44 mg portion (0.14) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 25 mg (0.14 mmol) of methyl 2-isocyanatobenzoate in 500 uL of THF followed by the addition of 1 equivalent of TEA (24 μL) and 1 equivalent of DBU. After 18 h, the mixture was purified by RP-HPLC, to give 21 mg (34%) of the desired compound. ES-MS (M+H)+=462 (Cl).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:31])([F:30])[C:23]#[C:24][C:25](OCC)=[O:26]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:25](=[O:26])[CH:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: CCO
Product: O=c1cc(C(F)(F)F)n2c(n1)OC(COc1ccc(C3CCCCC3)cc1)C2
Temperature: 170 °C
Yield: 25.3 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (165 mg, 0.602 mmol) in ethanol (6 mL) was added ethyl 4,4,4-trifluoro-2-butynoate (100 mg, 0.602 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 30 mins. Solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-10% EtOH/CH2Cl2) to afford 60 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-trifluoromethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as an off-white solid.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[CH2:33]([C:40]1[CH:44]=[N:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[N:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:33]([C:40]1[CH:44]=[N:43][N:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:47][CH2:46]2)[N:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(Cc2cnn(C3CCNCC3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3ncc(Cc4ccccc4)n3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 12 h
Yield: 42 %

Procedure:
A Solution of α-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, para-methoxybenzyl ester (52 mg, 0.12 mmol, (prepared above as Aldehyde 5)), 4-(4-benzyltriazol-2-yl)piperidine (41 mg, 0.17 mmol from Step C) and sodium triacetoxyborohydride, (51 mg 0.24 mmol) in 1 mL of 1,2-dichloroethane was stirred for 12 h. The solvent was removed and the product was purified by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 5% acetonitrile/water w/0.1% TFA for 1 min then ramp to 100% acetonitrile w/0.1% TFA over 6 min, flow: 20 mL/min). The so isolated material was stirred in 3 mL formic acid for 16 h. After removal of solvent the residue was purified by ion exchange chromatography (3 grams SCX resin, 100% MeOH→2.0M NH3/MeOH) to give 17 mg (42%) of the title compound. 1H NMR (500 MHz, CD3OD). δ1.0-3.6 (m, 29H), 4.05 (s, 2H), 7.15-7.35 (m, 10H), ESI-MS. M/z; (M+H)=542.4 (obs), 542.34 (calc.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(NC(C)C)(C)C.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:28])[O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Oc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (15.0 g) and diisopropylamine (16.2 ml) in dichloromethane (300 ml) was added dropwise under ice-cooling a solution of phenylchloroformate (16.8 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature overnight, washed with water and saturated saline and dried over anhydrous MgSO4. The solvent was distilled off. Crystallization of the residue from hexane gave phenyl 4-methoxy-2-nitrophenylcarbamate (12.6 g, 49.1%) as crystals.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1C)=[O:2].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O.C(=O)(O)[O-].[Na+].[OH-].[Na+].[Cl-].[Na+].O.[Cl-].[Na+]>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:8]([C:6]2[NH:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[O:10])[CH2:42][CH2:41]1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc(C=O)[nH]2)CC1

Procedure:
5-Formyl-4-methyl-1H-pyrrole-2-carboxylic acid was dissolved in dimethylformamide (0.3M) with stirring. To this was added 1-ethyl-3-(3-dimethylamino-propylcarbodiimide hydrochloride (1.2 equivalents), 1-hydroxybenzotriazole (1.2 equivalents) followed by triethylamine (2 equivalents) and 1-methylpiperazine (1 equivalent) and the reaction stirred for 12 hours (General Amidation Procedure 1). The reaction was diluted with saturated sodium bicarbonate solution, sodium hydroxide solution, brine, solid sodium chloride and extracted twice with 10% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was re-concentrated from toluene and precipitated from diethyl ether:hexanes to afford 5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a solid. MS m/z 222 [M+1].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:2][O:3][C:4](=[O:11])[C@@H:5](/[N:6]=[CH:17]/[C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)/N=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
L-Leucine methyl ester hydrochloride (3.65 g) was dissolved in methanol (35 mL) and 4-fluoro-benzaldehyde (2.65 mL) and Na2CO3 (4.0 g) were added. The mixture was stirred at ambient temperature for 3 days. After that, the mixture was filtrated, evaporated to dryness. The residue was dissolved in TBME. The precipitate was filtrated off. The TBME solution was evaporated to dryness to yield the title compound as a colorless oil (4.66 g; 92%). MS (ESI): m/z=252.3 [M+H]+.
Reaction SMILES: C1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])C=CC=CC=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:21])[NH2:23]
Reactant: N#C[O-]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)OCCCCC/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was dissolved in methylene chloride (20 ml), and sodium cyanate (0.50 g, 7.7 mmoles) and trifluoroacetic acid (5 ml) were added. The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was shaken with potassium carbonate (1 g), water (20 ml) and methylene chloride (50 ml), and the organic layer was separated, washed with water, dried and concentrated. Recrystallization of the residue from isopropyl ether gave 1-carbamoyloxy-(E)-7-(3-pyridyl)-6-heptene (1.82 g, 79%) (Compound Id-23).