Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:14][C:15](=O)[CH3:16].Cl.[C:19](O)(=O)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:15]3[CH2:16][CH2:19][CH2:14]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCNCC2)nc1
Reactant: CC(C)=O
Reactant: CC(=O)O
Agent: Cl
Solvent: CO
Product: Brc1ccc(C2CCN(C3CCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
5-Bromo-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl (6.4 g, 18.02 mmol) was dissolved in 2% acetic acid in MeOH (40 ml). Propanone (8 mL, 113 mmol) and Na(CN)BH3 (3.6 g, 57 mmol) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was added 1N HCl, filtered and concentrated in vacuo. The compound was dissolved in water and the pH was adjusted to 12, then extracted with DCM (3×200 mL). The crude product was treated with 1N HCl for 1 hour and extracted with diethyl ether to remove impurities. The aqueous phase was pH adjusted to pH=5.8-9. Extraction with ethyl acetate (3×100 mL) The organic phase was dried with Na2CO3, filtered and evaporation gave 4.6 g (86%) white crystals.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[BrH:17].C1(NC2CCCCC2)CCCCC1>ClCCCl.CCOC(C)=O.[Cu](Br)Br>[Br:17][C:4]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7](=[O:9])[O:8][C:3]=1[C@H:2]([OH:1])[CH2:15][OH:16]
Reactant: COC(=O)c1ccccc1C#C[C@H](O)CO
Reactant: Br
Agent: Br[Cu]Br
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=c1oc([C@H](O)CO)c(Br)c2ccccc12
Reaction time: 1.5 h
Yield: 309.3 %

Procedure:
A suspension of methyl 2-[(3S)-3,4-dihydroxy-1-butyn-1-yl]benzoate (500 mg, 2.270 mmol) in 1,2-Dichloroethane (DCE) (22 mL) was treated with dicyclohexylamine HBr (59.5 mg, 0.227 mmol) and then copper (II) bromide (1014 mg, 4.54 mmol) and stirred at 80° C. After 1.5 h, the reaction mixture was diluted with EtOAc, filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-70%) to afford the title compound (200 mg, 0.702 mmol, 31% yield) as brown solid: Rt=0.46 min,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([OH:11])[OH:10])=[CH:4][C:3]=1[F:13].O=[CH:15][CH:16]=O.C([O-])([O-])O[CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([O:10][CH2:15][CH3:16])[O:11][CH2:20][CH3:21])=[CH:4][C:3]=1[F:13]
Reactant: O=C(c1ccc(Br)c(F)c1)C(O)O
Reactant: CCOC([O-])[O-]
Reactant: O=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
To a mixture of 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone or 4-bromo-3-fluorophenyl)(oxo)acetaldehyde (7.0 g, 28 mmol) in toluene (50 mL) was added ethyl orthoformate (12 mL, 70 mmol) and p-toluenesulfonic acid (200 mg, 1 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Concentration under reduced pressure gave the desired product which was used in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:36])[CH:8]([O:33][CH2:34][CH3:35])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[C:29]([O:28][C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([O:33][CH2:34][CH3:35])[C:7]([OH:36])=[O:6])=[CH:15][CH:14]=2)=[CH:24][CH:23]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Lithium hydroxide hydrate (77 mg; 1.85 mmole) in water (5.5 ml) was slowly added to a solution of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (described in Example 38) (0.77 g; 1.68 mmole) in tetrahydrofuran (7.6 ml). After stirring at room temperature for 4 hours the reaction mixture was kept in a freezer for 4 days. Tetrahydrofuran was removed by evaporation in vacuo. More water was added and the mixture was acidified with hydrochloric acid to pH1. The product was extracted with ethyl acetate, washed twice with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 0.712 g (98.7% yield) of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28]O)[CH:3]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH:11]2[CH3:25])=[O:9])=[C:4]([CH2:28][Cl:32])[CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1CN(C(=O)COc2ccc(Cl)cc2CCl)C(C)CN1Cc1ccc(F)cc1
Yield: 91 %

Procedure:
To 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.55 g, 1.3 mmol) in methylene chloride (6 ml) was added thionyl chloride (0.26 ml, 3.58 mmol). The reaction was heated to reflux for 2 hours. After cooling the reaction was quenched by the addition of water. The organic layer was washed with saturated sodium bicarbonate followed by saturated aqueous sodium chloride. The organic layer was then concentrated to afford the title compound as a yellow oil (0.52 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[CH2:8][C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: N#CCC(=O)c1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A suspension of 4-bromobenzoylacetonitrile (500 mg) in ethanol (5 mL) and acetic acid (300 μL) was heated with sodium cyanoborohydride (280 mg) using an 80° C. hot plate for 2 hours. After cooling to ambient temperature, the mixture was diluted with water and concentrated to a syrup, which was diluted with ethyl acetate and washed with water, sat. NaHCO3, and brine. The extract was dried with MgSO4, filtered, and evaporated to provide 510 mg of a cloudy oil, which was filtered through silica gel using 1:1 ethyl acetate/hexane to provide the product (496 mg) as a thick oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].C(OC=[CH:12][C:13]([CH2:15][C:16](=[O:18])[CH3:17])=O)C.[K+].[Br-].N1C=CC=C[C:22]1=O>CO>[C:16]([C:15]1[CH:22]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:13]=1[CH3:12])(=[O:18])[CH3:17]
Reactant: CCOC=CC(=O)CC(C)=O
Reactant: O=c1cccc[nH]1
Reactant: N#CCC(N)=O
Agent: [Br-]
Agent: [K+]
Agent: [Na]
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Yield: 28 %

Procedure:
From cyanoacetamide (0.02 mol), sodium metal (0.02 g-atom) in MeOH (10 ml), and 5 (0.02 mol): 1.0 g, 28% yield; mp=233°-4° C.; NMR (DMSO-d6) δ 2.5 (s, 3H), 2.6 (s, 3H), 8.8 (s, 1H); IR (KBr), 1660 cm-1 (C=O of pyridone), 1690 cm-1 (C=O of ketone).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[O-:14][C:15]#[N:16].[K+].CN(C=O)C>[Br-].C([N+](CC)(CC)CC)C.O>[CH2:4]([CH:3]1[O:1][C:15](=[O:14])[NH:16][CH2:2]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC1CO1
Reactant: N#C[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC1CNC(=O)O1
Yield: 65.2 %

Procedure:
4.6 g of 1,2-epoxydodecane, 12.2 g of potassium cyanate, 25 ml of DMF, 0.2 g of tetraethylammonium bromide and 1.8 ml of water were stirred and heated at 120°-130° C. for 5 hours. The disappearance of the epoxide was followed by thin layer chromatography (tlc). The cooled reaction mixtre was poured into 200 ml of water and this was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated to give a solid. Recrystallization from methylene chloride/hexane gave 3.7 g (65.2%) of product, m.p. 86°-87° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][CH:29]=[N:28][CH:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH:40]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>O.O1CCOCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[NH:42]1[CH2:41][CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A microwave vial was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.076 g, 0.146 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.068 g, 0.219 mmol), Pd(AmPhos2)Cl2 (10.34 mg, 0.015 mmol), and potassium phosphate (0.093 g, 0.438 mmol). Dioxane (0.649 mL) and water (0.325 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred at 50° C. for one hour. The reaction was concentrated and the material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.069 g, 0.108 mmol) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (br. s., 1 H), 8.81 (br. s., 2 H), 8.70 (s, 1 H), 7.81-7.75 (m, 1 H), 7.63 (s, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.35 (s, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 7.06 (dd, J=2.1, 8.6 Hz, 1 H), 6.46 (d, J=8.6 Hz, 1 H), 5.86 (br. s., 1 H), 4.31 (d, J=4.1 Hz, 2 H), 3.66 (br. s., 2 H), 3.62 (t, J=4.1 Hz, 2 H), 3.17 (br. s., 3H), 2.42 (br. s., 1 H). m/z (ESI) 523.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=1)([O-])=O.Cl[Sn]Cl.O>O1CCOCC1.C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nsnc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2nsnc2c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of 5-nitrobenzo-2,1,3-thiadiazole in a mixture of dioxane (22 mL) and ethanol (22 mL) at RT added solid SnCl2 followed by addition of water (1 mL). The reaction mixture was warmed up to 50° C. and stirred for 10 min, cooled to RT, concentrated and partitioned between ethyl acetate/1 N NaOH. The organic layer was washed with 1N NaOH, water, brine, dried over MgSO4 and charcoal. Evaporation of the solvent gave 5-aminobenzo-2,1,3-thiadiazole as a yellow powder (3.0 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(CO)nc2cc(Br)cnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl)dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97°-100° C. (softening).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:29](=[O:30])[NH:28][CH2:26][CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: CCN=C=O
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.1 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (100 mg, 0.248 mmol) was suspended in dichloromethane (3.0 mL), and the suspension was added with triethylamine (0.104 mL, 0.744 mmol) and ethyl isocyanate (0.029 mL, 0.372 mmol), followed by stirring at room temperature for 13 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(ethylcarbamoylamino)propoxy]-7-iodoisoindolinone (100 mg, yield 93%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>CCOCC>[ClH:19].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:9]([CH:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[N:10]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CCN1CCC(c2nn(C(=O)c3ccc(Cl)cc3)c3cc(F)ccc23)CC1
Product: Cl
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 3.0 g of 3-(1-ethyl-4-piperidinyl)-6-fluoro-1H-indazole and 8 ml of 4-chlorobenzoyl chloride was heated at 100° C. in a steam bath for 4 hrs. Ether was added and the solid was collected. The solid was recrystallized twice from ethanol-ether to yield 2.9 g (57%) of product, mp 240°-242° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([Br:11])([F:10])[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)c1ccccc1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: FC(F)(Br)c1ccccc1Br
Reaction time: 72 h

Procedure:
A solution of 1-bromo-2-difluoromethylbenzene (9.6 g, 46.8 mmol) and N-bromosuccinimide (24.8 g, 139 mmol) in carbon tetrachloride (100 mL) was irradiated with a sunlamp. After 3 days, the reaction mixture was diluted with hexane, the precipitate was filtered off, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (100% hexanes) provided the title compound: 1H NMR (500 M=Hz, CD2Cl2) δ7.74 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (td, J=7.7, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([S:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:14])[CH2:11]3)[C:8]=2[C:15]([O:17]CC2C=CC([N+]([O-])=O)=CC=2)=[O:16])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:34]>O1CCOCC1.O.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:14])[CH2:11]3)[C:8]=2[C:15]([O-:17])=[O:16])=[CH:28][CH:29]=1.[Na+:34]
Reactant: Cc1ccc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(SC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1

Procedure:
A mixture of a solution of 70 mg of 4-nitrobenzyl 3-(4-methylthiophenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 13 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 35° for 60 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C1CCCCC1.C(OCC)(=O)C>[Pd].C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][C:2]([CH3:17])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCCCC1
Product: COC(=O)C(C)(C)Cc1cccc(N)c1
Reaction time: 12 h

Procedure:
At room temperature, 1 g of palladium on carbon (10%) was added to a solution of 12 g (51.42 mmol) of methyl 2,2-dimethyl-3-(3-nitrophenyl)propanoate in 200 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure for 12 hours. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 9.2 g (44.39 mmol, 86% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH2:33].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH:33][C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccccc1
Reactant: Cn1nccc1-c1c(Cl)sc(N)c1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CNC(=O)OC(C)(C)C)c2ccccc2)c1Cl
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol), [3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine (320 mg, 1.290 mmol) and DIPEA (1.126 ml, 6.45 mmol) in dichloromethane (12.100 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) in one portion. After 12 h, additional DIPEA (1.126 ml, 6.45 mmol), 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol) and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) were added and the solution stirred 24 h. The reaction mixture was then dry loaded onto silica and purified by chromatography (0-70% EtOAc in hexanes) affording 1,1-dimethylethyl (3-{[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-phenylpropyl)carbamate (320 mg, 0.491 mmol, 38.1% yield) as an yellow oil: LCMS (ES) m/e 495, 497 (M, M+2)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10]1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1 eq 1-(pyridin-2-ylmethyl)piperazine hydrochloride in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue re-dissolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude product is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](O)=[C:4]([O:10][C:11]2([CH2:14][OH:15])[CH2:13][CH2:12]2)[N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]1([CH:11]2[O:10][C:4]3[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=3[O:15][CH2:14]2)[CH2:12][CH2:16]1
Reactant: OCC1(Oc2nc(Cl)nc(Cl)c2O)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2c(n1)OC(C1CC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 2,4-dichloro-6-(1-hydroxymethyl-cyclopropoxy)-pyrimidin-5-ol (135 mg, 0.54 mmol) and triphenylphosphine (180 mg, 0.65 mmol) in THF (8 mL) was added DIAD (128 μL, 0.65 mmol) and the mixture stirred at RT for 30 minutes, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-25% ethyl acetate in cyclohexane) affording 7-Cyclopropyl-2,4-dichloro-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (90 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 4.30 (2H, s), 1.36-1.29 (2H, m), 1.01-0.95 (2H, m).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I-].[CH3:16][O:17][C:18]([CH2:20][CH2:21][CH2:22][Zn+])=[O:19]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([CH2:22][CH2:21][CH2:20][C:18]([O:17][CH3:16])=[O:19])[CH:14]=[CH:13][CH:12]=1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Reactant: COC(=O)CCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: COC(=O)CCCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
A mixture of tert-butyl 3-iodobenzoate (2 g, 6.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.329 mmol) in THF (10 ml) was treated with a freshly prepared 3-methoxycarbonylpropylzinc iodide (0.25 M in THF, 27 ml, 6.58 mmol). The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous ammonium chloride (5 ml) and extracted with diethyl ether. The organic phase was washed with saturated aqueous ammonium chloride, brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=9:1) to give the title material (0.73 g, 40%) as a colorless oil.