Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH3:8])=[O:6].[CH3:9][NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17]O)=[CH:14][CH:13]=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[CH3:9][NH:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][S:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: CNCc1ccc(CO)o1
Reactant: CNC(=O)NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNCc1ccc(CSCCNC(=O)NC)o1
Reaction time: 24 h
Yield: 11.5 %

Procedure:
To a stirred solution of N-[2-mercaptoethyl]-N'-methylurea (2.0 g) in concentrated hydrochloric acid at 0° was added dropwise a solution of 5-(methylamino)methyl-2-furanmethanol (2.0 g) in water (3 ml). After 24 hr, ethyl acetate (100 ml) and excess anhydrous sodium carbonate were added. The suspension was filtered, the filtrate evaporated to dryness and the oily residue column chromatographed (silica/methanol:0.88 ammonia 79:1). The relevant eluate was evaporated to dryness to give an oil identical to product of Example 4 (0.42 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9]Br)=[CH:4][C:3]=1[O:12][CH3:13].[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]=[C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:9]=2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: Nc1ncccn1
Reactant: COc1cc(C(=O)CBr)ccc1O
Solvent: CC#N
Product: COc1cc(-c2cn3cccnc3n2)ccc1O
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To 30 ml of an acetonitrile solution of 3.9 g (16 mmol) of 4′-hydroxy-3′-methoxy-2-bromoacetophenone was added 3.2 g (34 mmol) of 2-aminopyrimidine, and the mixture was stirred at 65° C. for 2 hours. The precipitated crystals were suction filtered and dissolved in 100 ml of 50% methanol. This solution was mixed with 1.3 g of sodium hydrogencarbonate and stirred at room temperature for 10 minutes. The precipitated crystals were suction filtered, and recrystallized from 50 ml of 50% methanol, thereby giving 2.4 g of 2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]pyrimidine in an yield of 62%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:20]([NH:23][CH:24]1[CH2:28][CH:27]([CH3:29])[NH:26][CH2:25]1)(=[O:22])[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH:27]([CH3:29])[CH2:28][CH:24]([NH:23][C:20](=[O:22])[CH3:21])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC1CNC(C)C1
Product: CC(=O)NC1CC(C)N(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
The condensation of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3-acetamido-5-methylpyrrolidine in a similar manner as described in example 1 give the titled product. Yield (68%), m.p 270–72° C., C20H22FN3O4, m/z 388 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=O)[CH2:12][CH2:11]2)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.Cl.[O:27]([NH2:29])[CH3:28]>C(O)C>[CH3:28][O:27][N:29]=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:3]2[C:2]([Br:1])=[CH:6][N:5]([CH3:7])[N:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cn1cc(Br)c(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)n1
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(CN1CCN(C(=O)c2nn(C)cc2Br)CC1)c1ccc(F)cc1
Temperature: 90 °C
Yield: 23.8 %

Procedure:
2-(4-(4-Bromo-1-methyl-1H-pyrazole-3-carbonyl)piperazin-1-yl)-1-(4-fluorophenyl)ethanone (100 mg, 0.24 mmol) and methoxylamine hydrochloride (25 mg, 0.31 mmol) were taken up in ethanol (10 mL) in a round-bottom flask and heated to reflux at 90° C. for 21 h. The solvent was removed under reduced pressure and saturated aqueous NaHCO3 (1.5 mL) was added. The mixture was extracted three times with DCM and the organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative TLC plate (Rf=0.44, 60% EtOAc/Hexane, UV 254 nm) and dried to afford the title compound (25 mg) as a free base. 1H NMR (Acetonitrile-d3, 400 MHz) δ 2.42-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.35-3.42 (m, 2H), 3.37 (s, 2H), 3.57-3.63 (m, 2H), 3.80 (s, 3H), 3.84 (s, 3H), 7.14 (t, J=8.84 Hz, 2H), 7.60 (dd, J=5.31, 8.84 Hz, 2H), 7.61 (s, 1H). Exact mass calculated for C18H21BrFN5O2: 437.1. Found: LCMS m/z (%)=438.3 (M+H+79Br, 100%), 440.3 (M+H+81Br, 97%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][C:7]1[CH:8]=[C:9]([B:13]2[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[CH3:19][C:16]1([CH3:20])[CH2:15][O:14][B:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[CH2:6][NH:4][CH:1]([CH3:3])[CH3:2])[O:18][CH2:17]1
Reactant: CC(C)N
Reactant: CC1(C)COB(c2cccc(CBr)c2)OC1
Solvent: ClCCl
Product: CC(C)NCc1cccc(B2OCC(C)(C)CO2)c1
Temperature: 23 °C
Yield: 89.3 %

Procedure:
To a solution of isopropylamine (15 mL, 10 g, 180 mmol, 10 eq) in dichloromethane (100 mL) was added dropwise a suspension of 2-[3-(bromomethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane (5.0 g, 18 mmol, 1.0 eq) in dichloromethane (75 mL) over 1 hour. After the addition was complete the reaction was stirred for an additional hour at 23° C. and then the reaction solution was washed with brine, dried over sodium sulfate and concentrated to yield N-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl]propan-2-amine (4.2 g, 91%) as a clear oil. LRMS m/z (M+H) 516.2 found, 262.2 required.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]2[CH2:12][O:11]2)[CH:8]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[CH2:12][CH:10]([OH:11])[CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1
Reactant: CNC
Reactant: O=[N+]([O-])c1cnn(CC2CO2)c1
Product: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1

Procedure:
4-nitro-1-(oxiran-2-ylmethyl)-1H-pyrazole (200 mg, 1.2 mmol) was stirred overnight at rt in dimethylamine (2M in methanol, 5 mL). The solution was concentrated to give 1-(dimethylamino)-3-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow solid (quantitative). LC-MS (UPLC, high pH), (ES+) 215.2, RT=0.75 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CS(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: ClCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.39 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 21 mL of dimethyl sulfoxide, under an argon atmosphere with stirring, is added 0.336 g of 60% sodium hydride in oil. This mixture is stirred for 1.5 hours. To the resulting solution is added 1.32 g of 1-bromo-3-chloropropane and this reaction mixture is stirred for 3 hours and is next poured into 100 mL of ice water. This mixture is twice extracted with diethyl ether and the combined organic extracts dried with magnesium sulfate. The organic solution is filtered, and concentrated in vacuo to give the desired compound as a golden oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12].CO.[Cl:15][O-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][Cl:15]
Reactant: [O-]Cl
Reactant: Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)c(CCl)c(Cl)c1
Reaction time: 3.75 h

Procedure:
A solution of 2,6-dichloro-4-nitrotoluene (2.0 g 9.7 mmol) in tetrahydrofuran: methanol mixture (20:11 cm3) was added slowly to a vigorously stirred solution of 10-14% aqueous sodium hypochlorite (15 cm3) at 0° C. After 3.75 h at this temperature, the mixture was poured into dilute hydrochloric acid and then extracted with chloroform (30 cm3). The organic extract was dried and evaporated to yield an organge oil which was purified by flash chromatography over silica gel eluting with an ethyl acetate-petroleum ether gradient. The title compound was obtained as a pale orange solid, m.p. 37°-9° C. (1.8 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:22]([CH2:29][CH2:30][CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:22]([CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1O
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCc3ccccc32)cc1OCCCOc1ccccc1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
A solution of N-(3-hydroxy-4-methoxybenzenesulphonyl)- 1,2-dihydroindole (0.2 g) and 3-phenoxypropylbromide (0.15 g) in N,N-dimethylformamide (20 ml) was treated with cesium carbonate (0.3 g) and heated at 75° C. overnight. The solvent was removed in vacuo and the residue partitioned between dichloromethane (30 ml) and water (15 ml). The organic phase was washed with brine (15 ml) then dried over magnesium sulphate and concentrated in vacuo. The residue was purified using column chromatography eluting with dichloromethane to yield the title compound as a white solid (0.25 g).
Reaction SMILES: ClC1C=C(CCC(C2C=CC=CC=2)=O)C=CC=1Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28]/[C:29](/[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: O=C(CCc1ccc(Cl)c(Cl)c1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(3,4-dichlorophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(3,4-dichlorophenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(3,4-dichlorophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]#[N:6].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:28][N:27]=[N:26][N:6]=2)[CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11]
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nnn[nH]2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzonitrile (0.348 g) in dimethylformamide (2 ml) was added sodium azide (0.078 g) and ammonium chloride (0.065 g). The mixture was heated to 100° C. for 18 hours.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[O:18][C:19]1[C:20]([F:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>CN(C=O)C>[F:29][C:20]1[C:19]([O:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:37]4[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([CH3:28])[NH:24]2
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 22.6 %

Procedure:
A solution of 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (0.3 g, 0.652 mmol) and 1-(methylsulphonyl)piperazine (0.322 g, 1.95 mmol), (prepared as described for the starting material in Example 2), in DMF (4 ml) was stirred at 80° C. for 2.5 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.08 g, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1.N1C=CC=CC=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: OCCCc1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of 3-(5-Bromo-2-fluoro-phenyl)-propan-1-ol (0.53 g, 2.3 mmol) in dry methylene chloride (10 mL) at 0° C. and under a nitrogen atmosphere was added pyridine (0.46 mL, 5.6 mmol) and tosyl chloride (0.47, 2.5 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 12 h, and then quenched with 2 N HCl (6 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-20% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.6 g, 69%) as a clear oil, identified by NMR and mass spectral analyses; MS (ES+): 403 (M+NH4+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][O:15][N:16]=[C:17]([CH:19]2[C:24](=[O:25])[CH2:23][CH:22]([CH:26]3[CH2:31][CH2:30][CH2:29][S:28][CH2:27]3)[CH2:21][C:20]2=[O:32])[CH3:18])=[CH:11][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:25][C:24]1[CH2:23][CH:22]([CH:26]2[CH2:31][CH2:30][CH2:29][S:28][CH2:27]2)[CH2:21][C:20](=[O:32])[C:19]=1[C:17](=[N:16][O:15][CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(=NOCc1ccc(Cl)s1)C1C(=O)CC(C2CCCSC2)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
In this example, 0.52 g (5.1 mmol) of triethylamine was admixed to a solution containing 1.46 g (3.7 mmol) of 2-[1-[(5-chlorothien-2-yl)methoxyimino]ethyl]-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohexane-1,3-dione in 30 ml of methylene chloride at room temperature (about 20°-25° C.) followed by the dropwise addition of 0.35 g (4.4 mmol) of acetyl chloride. The mixture was stirred at room temperature overnight (about 14 hours) and then washed with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica gel to afford 1.0 g of the title compound as a yellow oil; IR (neat) 1775 cm-1 ; 1H NMR spectrum (90 MHz CDCl3) δ1.00-2.60 (m, 14H), 1.93 (s, 3H), 2.00 (s, 3H), 5.07 (s, 2H) 6.73 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:11]=[CH:10][N:9]=1.[CH3:28][C:29]1([CH3:42])[O:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:31][O:30]1>CN(C=O)C>[CH3:28][C:29]1([CH3:42])[O:30][CH2:31][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:8]3[C:13]([CH3:14])=[C:12]([O:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]5[N:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:18][CH2:17]4)[N:11]=[CH:10][N:9]=3)=[CH:37][CH:36]=2)[CH2:33][O:34]1
Reactant: Cc1c(Cl)ncnc1OC1CCN(c2ncccn2)CC1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(C3COC(C)(C)OC3)cc2)ncnc1OC1CCN(c2ncccn2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
Cesium carbonate (2.97 mg, 0.00914 moles) was added to a solution 4-chloro-5-methyl-6-(1-(pyrimidin-2-yl)piperidin-4-yloxy)pyrimidine (1.39 gm, 0.00457 moles) and 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (950 mg, 0.00457 moles) in dry DMF (10 ml) and the reaction mixture was stirred at 60° C. for 12 hours. Then reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product so obtained was purified by column chromatography (silica gel) using 22% ethyl acetate in hexane as eluent to obtain 1.5 gm product as white solid.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:5]=1)[CH3:3].[BH4-].C([N+](CC)(CC)CC)C.C(COC)[O:33]C>CO.C1C=CC(C2C3=NC(C=C3)=C(C3C=CC=CC=3)C3[N-]C(=CC=3)C(C3C=CC=CC=3)=C3C=CC(=N3)C(C3C=CC=CC=3)=C3[N-]C=2C=C3)=CC=1.[Co+2]>[OH:33][C:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:1]
Reactant: COCCOC
Reactant: C=C(C)c1nn(-c2ccsc2)c2cc(C(=O)OC)ccc12
Agent: [Co+2]
Agent: C1=Cc2nc1c(-c1ccccc1)c1ccc([n-]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([n-]3)c2-c2ccccc2)C=C1
Agent: CC[N+](CC)(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(C(C)(C)O)nn(-c3ccsc3)c2c1
Reaction time: 1.25 h
Yield: 80 %

Procedure:
Methyl 3-(prop-1-en-2-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylate (1.0763 g, 3.61 mmol) was dissolved in dimethoxyethane (90 ml)/MeOH (90 ml) at 25° C. Cobalt(II) meso-tetraphenylporphine (25.6 mg, 0.038 mmol) and tetraethylammonium borohydride (1.316 g, 9.07 mmol) were added sequentially. The reaction mixture was allowed to stir for 1.25 h. The reaction was stopped, quenched by addition of saturated aqueous ammonium chloride (100 mL), and the mixture extracted with ethyl acetate (3×80 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×80 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 330 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-45%). The title compound (912.2 mg, 2.88 mmol, 80% yield) was recovered as an orange solid. LC-MS: [M+1]=317.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].O1CCOCC1>C(Cl)Cl>[ClH:32].[ClH:32].[O:24]1[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:21][CH2:20]2)=[N:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{trans-4-[2-(4-Isoxazolo[4,5-c]pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (930 mg, 2.2 mmol) was dissolved in CH2Cl2 (3 ml) and 4 N HCl in dioxane (10.8 ml, 43 mmol) was added. The resulting mixture was stirred 16 h at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 686 mg (79%) as a white solid. m/z=330.3 ([M+H]+).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH3+:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:11]=1[O:23][C:24](=[O:27])[NH:25][CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([O:42][C:43]([NH:45][C@@H:46]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:52]=1)[C:47](O)=[O:48])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:21][O:20][C:18](=[O:19])[C@@H:17]([NH:22][C:47](=[O:48])[C@@H:46]([NH:45][C:43]([O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:52]=1)[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:11]([O:23][C:24](=[O:27])[NH:25][CH3:26])[CH:12]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O)OCc1ccccc1
Reactant: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)Oc1cc(C[C@H](NC(=O)[C@H](Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)NC(=O)OCc2ccccc2)C(=O)OC)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-2-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride (0.2 g, 0.506 mmol) was suspended in dichloromethane (20 ml), then triethylamine (0.068 g, 0.678 mmol) was added, followed by the addition of (S)-2-benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionic acid (0.31 g, 0.678 mmol) [see German patent DE 2121187] and HOBt (0.092 g, 0.678 mmol). The mixture was stirred at room temperature for 20 min. EDC (0.130 g, 0.678 mmol) was added. The stirring was continued overnight. The mixture was washed with sodium bicarbonate, dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (1:2). (S)-2-[(S)-2-benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionylamino]-3-(4-benzyloxy-3-methylcarbamoyloxy-phenyl)-propionic acid methyl ester was obtained as a white solid, 0.43 g. 1H NMR (400 MHz, CDCl3) 2.62 (d, J=4.6 Hz, 3H), 2.88-3.00 (m, 3H), 3.35 (s, 1H), 3.56 (s, 3H), 4.24-4.30 (m, 1H), 4.43-4.49 (m, 1H), 4.95 (m, 2H), 5.06 (m, 6H), 6.80 (m, 1H), 6.92-7.09 (m, 5H), 7.23-7.45 (m, 21H), 7.59 (m, 1H), 8.46 (d, J=7.3 Hz, 1H).