Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([OH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:10]=[N+:11]=[N-:12].[Na+]>CCO.O>[N:10]([CH2:2][CH:3]([OH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N+:11]=[N-:12]
Reactant: CCOC(=O)C(O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)CN=[N+]=[N-]
Temperature: 90 °C

Procedure:
To a solution of ethyl 3-bromo-2-hydroxypropanoate (22.1 g, 112.0 mmol) in EtOH/H2O (1:1) was added sodium azide (10.9 g, 168.0 mmol). The reaction was stirred and heated to 90° C. for 3 days. The EtOH was removed in vacuo and the remaining aqueous solution was extracted with CHCl3 several times. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the azide as an orange oil. 1H NMR (400 MHz, d6-DMSO) δ 5.96 (d, J=5.6 Hz, 1H), 4.31-4.28 (m, 1H), 4.19-4.08 (m, 2H), 3.51-3.40 (m, 2H), 1.28-1.17 (m, 3H).
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.[CH3:19][S:20](Cl)=[O:21]>C(OCC)C>[CH3:19][S:20]([N:11]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:21]
Reactant: CS(=O)Cl
Reactant: C1CCC2CCCC(C1)N2
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)N1C2CCCCC1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of 10-azabicyclo[4.3.1]decane hydrochloride (10 mg, 0.057 mmol) in anhydrous diethyl ether (1 mL) was cooled in an ice bath. The reaction mixture was treated with triethylamine (0.1 mL, 0.72 mmol) and methanesulfinyl chloride (10 mg, 0.1 mmol). The reaction vial was sealed and placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temp, diluted with ether (2 mL), washed with water (2×1 mL), sat. aq. KCl (1×2 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as an oil (8.1 mg, 71%): 1H NMR (CDCl3, 600 MHz, δ) 4.02 (br quin, 1H, J=4 Hz, C1- or C9-H), 3.84 (br quin, 1H, J=4 Hz, C1- or C9-H), 2.55 (s, 3H, C1′H), 1.88-1.72 (m, 5H), 1.65-1.48 (m, 9H); ESIMS m/z 224.1 (89, MNa+), 202.1 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Cl)cc(C=O)c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(Cl)cc(C=O)c1OC
Temperature: 61 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A mixture of 5-Chloro-2-hydroxy-3-methoxybenzaldehyde (275 g, 1.47 mol) and DMF were stirred as potassium carbonate (411 g, 2.97 mol) was added over 5 minutes. The mixture temperature rose from 22 to 29° C. over 10 minutes. Dimethylsulfate (283 g, 2.24 mol) was added over 15 minutes causing a temperature rise from 28 to 47° C. The mixture was then heated with a heating mantle to 61° C. over 15 minutes and stirred at 61° C. for 1.5 hours; the reaction was complete by TLC. The reaction mixture was cooled to 22° C., transferred to a 22-L flask and diluted with water (8.2 L) over 5 minutes; the temperature rose to 38° C. The light yellow mixture was filtered and the flask and filter cake rinsed with 1.5 L water. The solid was dried under vacuum for 15 hour at 50° C. The material contained inorganic salts and was suspended in water (3 L) for 1.5 hours. After filtration and a 500 mL water rinse, the filter cake was dried under by suction and overnight at 65° C. under vacuum. Yield: 305 g (100% yield, 99.1% purity).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[Li+].[CH3:22]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([CH3:22])=[CH:10][C:3]=12
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (D20) (6 g, 17.08 mmol) in THF (100 ml) was cooled to −78° C. LDA (2M in THF) (21.35 mL, 42.7 mmol) was added at −78° C. and stirred at this temperature for ca. 1 hour. Iodomethane (2.136 ml, 34.2 mmol) was then added. After stirred at −78° C. for further ca. 30 min, the mixture was quenched by addition of saturated NH4Cl solution (150 mL), extracted with ethyl acetate (100 mL×3). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound containing impurities (5.4 g). LCMS (A): m/z (M+H)+ 365/367, C15H13BrN2O2S requires 364/366 (acidic).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=O)[N:13]([C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[NH2:25])[CH:14]([CH3:16])[CH3:15])(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH:14]([CH3:16])[CH3:15])[C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[N:25]=1
Reactant: CC(C)N(C(=O)CCCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1c(CCCCN)nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
The compound (44.1 mg) obtained in Example 47-1 was dissolved in anhydrous methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (26.0 mg) as a white crystal.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][N:22]=1>C(COC)OC>[CH2:1]([N:8]([CH2:23][C:20]1[S:19][C:18]([Cl:17])=[N:22][CH:21]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Reactant: ClCc1cnc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2cnc(Cl)s2)CO1
Temperature: 50 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.3 g of sodium hydroxide are added and, at 40° C., 34.4 g of a 15% solution of 2-chloro-5-(chloromethyl)-1,3-thiazole in dimethoxyethane are metered in. The mixture is stirred at 50° C. for a further 6 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 6.9 g of 4-{benzyl[(2-chloro-1,3-thiazol-5-yl)methyl]amino}furan-2(5H)-one are obtained (this corresponds to 71% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:44]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:45])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using cyclopentanecarbonyl chloride. The final product was obtained in 57% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[C:6]=2[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:60][CH2:61][O:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=4[CH3:69])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[C:6]=2[CH:39]=1
Reactant: Cc1ccccc1OCCO
Reactant: COc1cc(NC(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonyl-methyl]-1-(2-methoxy-4-trifluoroacetylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dry tetrahydrofuran (20 ml) are added triphenyl-phosphine (0.54 g) and o-(2-hydroxyethoxy)toluene (0.29 g) at room temperature. To the mixture is added dropwise a solution of diethyl azodicarboxylate (0.32 ml) in dry tetrahydrofuran (5 ml), and the mixture is stirred at room temperature for 16 hours. To the mixture is added water, and the mixture is extracted with diethyl ether. The ether layer is dried, evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1→30:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.46 g) as colorless amorphous.
Reaction SMILES: C([O:4][C:5]1([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH2:10][NH:9][C:8](=[O:11])[CH:7]=[C:6]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][C:5]1([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH2:10][NH:9][C:8](=[O:11])[CH:7]=[C:6]1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1(c2cccc(C)c2)CNC(=O)C=C1c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C2(O)CNC(=O)C=C2c2ccncc2)c1
Reaction time: 1 h

Procedure:
To a solution of 5-acetoxy-5-m-tolyl-5,6-dihydro-1H-[4,4′]bipyridinyl-2-one (322 mg, 1.0 mmole) in THF (5 mL) and water (5 mL) at r.t. was added LiOH (126 mg, 3.0 mmole) in one portion. The reaction mixture was stirred at that temperature for 1 hr before quenching the mixture with aqueous NH4Cl. Standard work up (extraction of compound with methylene chloride), followed by purification (methano/methylene chloride) gave the title compound. MS (m/z): Calcd. C17H16N2O2(M+): 280, found (M+H)+: 281.0.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O>C(O)C>[CH2:11]([O:19][C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:6][CH:5]=1)[CH3:10]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
0.5 g (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one, 5 ml ethanol and 0.3 ml perchloric acid were heated at about 80-120° C. for about 24 hours. The mixture was evaporated to dryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (perchlorate salt). 1H NMR (CDCl3): 1.17 (3H), 1.20 (3H), 1.98 (2H), 2.76 (1H), 2.96 (1H), 3.29 (1H), 3.82 (1H), 3.96 (2H), 7.32-7.59 (13H), 8.21 (3H).
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:5]([O:6][C:7]2[C:8]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=2)=[C:4]([N+:36]([O-])=O)[CH:3]=1.C(O)C>[Pt]=O.C(OCC)(=O)C>[NH2:36][C:4]1[CH:3]=[C:2]([F:1])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:5]=1[O:6][C:7]1[C:8]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, platinum oxide, ethanol and ethyl acetate is stirred for 1.5 hours at room temperature under hydrogen atmosphere. The reaction system is purged with nitrogen, then, the reaction solution is filtrated through Celite, and the filtrate is concentrated to obtain 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(N2[C:23]([C:24]3[CH:29]=[C:28](F)[CH:27]=[C:26]([Cl:31])[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=N2)C=CC=1F>>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Br)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 3A and 3-bromophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.50 g of the title compound with 70% purity (67% of theory) are obtained.
Reaction SMILES: O.O.Cl.[CH:4]1([C:10]([N:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:37])=[O:36])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH3:47]>CN(C=O)C>[CH:4]1([C:10]([N:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][CH2:45][CH2:46][CH3:47])=[O:36])[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:19][CH2:20]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C(=O)O)CC1
Reactant: CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1ccccc1N(CCN1CCN(c2ccccc2OC)CC1)C(=O)C1CCCCC1
Yield: 62 %

Procedure:
A mixture of 0.17 g of the compound 49A of example 49, 0.14 g of anhydrous potassium carbonate, 0.2 mL of 1-bromopropane and 3 ml, of DMF was stirred at 60° C. under nitrogen atmosphere for 6 h. The cooled mixture was filtered, poured into 50 mL of H2O and extracted with EtOAc. The organic layer, dried on anhydrous Na2SO4, was evaporated to dryness to give 0.10 g (62%) of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH3:23])([O-:13])=[O:12].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:23][C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a 2 liter 3-necked round-bottomed flask equipped with a condenser, a Dean-Stark trap, a mechanical stirrer, nitrogen inlet, heating mantle, thermometer, and a Therm-o-watch® temperature controller, was added p-anisaldehyde (149.8 grams, 1.1 moles), 2,4-dinitrotoluene (182 grams, 1.0 mole), xylene (500 milliliters), and piperidine (50 milliliters, 0.5 mole). The resulting mixture was heated with the temperature on the Therm-o-watch® temperature controller set at 145° C. After stirring and heating for about 2 hours, approximately 20 milliliters of water had collected in the Dean-Stark trap. The reaction solution was allowed to cool to room temperature, and then further cooled with an ice water bath for an additional hour during which time the desired product crystallized from the solution. The solid material was filtered, rinsed with pentane, and dried in a vacuum oven at 100° C. for 12 hours to give 257.1 grams (85.6 percent of theory) of the desired product as a dark red crystalline solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([C:10]([O:12]CC)=O)=[C:7](Cl)[N:8]=1.Cl.[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[NH:24])[CH:17]([CH3:19])[CH3:18]>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]2[C:10](=[O:12])[NH:25][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[N:24][C:7]=2[N:8]=1
Reactant: CC(C)COc1ccccc1C(=N)N
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CSc1nnc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1

Procedure:
In a similar manner to Example 85 reaction of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.5 g) with 2-isobutoxybenzamidine hydrochloride (2.37 g) and triethylamine (1.75 g) afforded the crude title compound (1.71 g). This was recrystallized from acetonitrile, then dissolved in chloroform, the organic solution was washed with 2 Normal hydrochloric acid (×2), chloroform removed under reduced pressure and the residue recrystallized twice from ethanol to afford the title compound, 0.32 g, m.p. 237-238° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][O:46][CH3:45])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: COCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (2.5 mg, 18%). MS (m/e): 341.3 (MH+).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
To a solution of 3-buten-1-ol (540 mg, 7.5 mmol) and sodium hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to yield 650 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc5[nH]ccc45)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 74) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan solid as a mixture of diastereomers (0.95 g, 64%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:21].[CH3:25][CH:26](O)[CH2:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1>C(Cl)Cl>[CH3:36][C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([CH3:35])[CH:32]=1)[O:28][CH2:27][CH:26]([Br:21])[CH3:25]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)cc(OCC(C)O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)cc(OCC(C)Br)c1
Yield: 74 %

Procedure:
0.94 Gram (3.6 mmol) of triphenylphosphine and 1.49 g (4.5 mmol) of carbon tetrabromide were added to a solution prepared by dissolving 0.54 g (3 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethanol in 10 ml of methylene chloride, and the resultant mixture was stirred at room temperature for 30 minutes. After the reaction, the solid was separated by filtration, and the remaining methylene chloride solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 (v/v)) to give 0.54 g of 1-(3,5-dimethylphenoxy)-2-bromopropane (yield 74.7%).