Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2([CH2:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: NC(=O)CC1(N)CCCCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1

Procedure:
2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide was prepared from 2-(1-Amino-cyclohexyl)-acetamide (2.0 g, 0.013 mol) (Suzuki, T.; Imanishi, N. Itahana, H.; Watauki, S.; Ohta, M.; Mase, T., Synthetic Communications, 1988, 28(4), 701-712) and 2,4,5-Trichloro-pyrimidine (1.5 mL, 0.013 mol) in an analogous manner to Example 1d. Product isolated as a white solid (2.28 g, 59%). MP: 124-128° C. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 8.19 (s, 1H), 7.51 (br s, 1H), 7.34 (br s, 1H), 7.04 (br s, 1H), 2.62 (s, 2H), 2.58-2.52 (m, 2H), 1.55-1.30 (m, 8H). MS: 303.00 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:35]([N:37]([CH2:40][CH2:41]Cl)[CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:35]([N:37]([CH2:40][CH2:41][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:10])[CH2:38][CH3:39])[CH3:36]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 49.6 %

Procedure:
A mixture of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (320 mg, 0.65 mmol), 2-[(N,N-diethyl)amino]ethyl chloride hydrochloride (579 mg, 3.26 mmol) and potassium carbonate (451 mg, 3.27 mmol) in ethyl acetate (5 mL) and water (5 mL) was at room termperature overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to afford N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester (190 mg, 49%) as an amorphous white solid. ES-HRMS m/e calcd for C29H34Cl2N4O5 (M+H) 589.1978, found 589.1980.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>C(N)CC1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][CH2:6][C:5]4[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: NCCc1ccccc1
Solvent: CCO
Product: O[C@H](CNCCc1ccccc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and phenethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=407.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1.N>ClCCl.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:4]2[N:3]=1
Reactant: Cc1cc2nc(Cl)c(-c3ccccc3)c(Cl)n2n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2nc(Cl)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.47 g 5,7-dichloro-2-methyl-6-phenylpyrazolo[1,5-a]pyrimidine is dissolved in 80 ml dichloromethane. 80 ml brine, 40 ml ammonia solution 25% w/w and 2.47 g zinc powder are added and the mixture is stirred at room temperature for 2 d. Four additional portions of 4.2 equivalents zinc powder are added over 4 days. The reaction mixture is filtrated over kieselgur and washed with dichloromethane and water. The organic phase is separated and the water phase extracted with dichloromethane. The combined dichloromethane phase is dried over Na2SO4 and the solvent is evaporated. The residue is purified on silica gel (dichloromethane/ethyl acetate) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:27]([CH2:35][CH2:36][CH3:37])[C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH3:26]>>[CH2:35]([N:27]([CH2:24][CH2:25][CH3:26])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32])[CH2:36][CH3:37]
Reactant: CCCN(CCC)C(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCN(CCC)C(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-(dipropylamino)-4-oxobutanoic acid to yield (3aR,4S,7aR)-methyl 4-(4-(dipropylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.771 min; LC/MS LC-MS Method III
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1([CH3:12])[O:11][CH2:10]1>C(Cl)Cl>[OH:11][CH2:10][C:9]1([CH3:12])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CC1(Cc2ccccc2O)CO1
Solvent: ClCCl
Product: CC1(CO)Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
A mixture of 1-(2-hydroxyphenyl)-2-methyl-2,3-epoxypropane (52.7 g) and silica (Kieselgel 60; 70-230 mesh) (150 g) in methylene chloride (300 ml) was stirred at room temperature for 24 hours. Removal of the solvent gave a residue of silica and absorbed product and this mixture was stirred with ethyl acetate for 3 hours. After filtration the ethyl acetate filtrate was dried and the solvent evaporated in vacuo to give the desired alcohol 49.6 g. This crude product was dissolved in methylene chloride and washed with 1 N aqueous sodium hydroxide solution, water and then dried. Removal of the solvent gave the alcohol as a yellow oil 37 g; I.R. νmax 3700-3200 cms-1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.Cl[C:32]1[CH:40]=[C:39](Cl)[CH:38]=[CH:37][C:33]=1C(Cl)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:33]=1)=[O:6]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
Sodium Hydride (60% dispersion in oil, 80 mg, 1.5 mmol) was added to an ice-cold solution 5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester (2) (230 mg, 0.74 mmol) in 20 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2,4-Dichloro-benzoyl chloride (310 mg, 1.48 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 16 h at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×10 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 58 mg (16%) of 3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65-7.10 ppm (m, 14H, Haro); 3.77 ppm (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[S:28]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29]1.Cl>C1COCC1.CS(C)=O.O>[S:28]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:8][CH2:7][C:4]([OH:6])=[O:5])=[CH:29]1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CC=Cc1ccsc1
Temperature: -60 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a stirring suspension of 1.60 g (67 mmol) of NaH in 20 mL of THF cooled to -60° C. was added a solution of 12.36 g (33 mmol) of (2-carboxyethyl)triphenylphosphonium chloride (28), prepared in the manner described above in Example 28, and 3.75 g (33 mmol) of 3-thiophene carboxaldehyde in 40 mL of dimethylsulfoxide (DMSO)/THF (3:1). The reaction was stirred for 16 hours at -20° C., and then for 6 hours at 0° C. The reaction was then added to cold H2O. The pH was adjusted to 2 with 2N HCl. The aqueous layer was extracted with 4×200 mL of EtOAc. The organic layer was treated as described above in Example 14 and chromatographed to yield 3.41 g (61%) of 4-(3-thienyl)-3-butenoic acid (29).
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]([C@:14]1([OH:34])[C@@:18]2([CH3:33])[CH2:19][CH2:20][C@@H:21]3[C@:31]4([CH3:32])[C:25](=[CH:26][C:27]([CH2:29][CH2:30]4)=[O:28])[CH2:24][CH2:23][C@H:22]3[C@@H:17]2[CH2:16][CH2:15]1)=[O:13]>C(Cl)(Cl)Cl.C(OCOCC)C>[OH:34][C@:14]1([C@:18]2([CH3:33])[C@H:17]([C@H:22]3[C@H:21]([CH2:20][CH2:19]2)[C@:31]2([CH3:32])[C:25](=[CH:26][C:27](=[O:28])[CH2:29][CH2:30]2)[C:24](=[CH2:1])[CH2:23]3)[CH2:16][CH2:15]1)[C:12](=[O:13])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 65 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of chloroform, 30 ml of formaldehyde diethylacetal, and 3.8 ml of phosphorus oxychloride is agitated in a two-necked flask for 1 hour at a bath temperature of 65° C. and then combined with 1.0 g of 17α-hydroxyprogesterone. The mixture is stirred for 1.5 hours at 65° C., cooled to room temperature, and under vigorous agitation a saturated soda solution is added dropwise until alkaline reaction occurs. The organic phase is separated, washed neutral with water, dried over sodium sulfate, and concentrated under vacuum. The crude product is purified on 220 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone), thus obtaining 842 mg of 17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 218°-220° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH:12]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)([CH3:14])[CH3:13].P(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CC(C)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1O
Temperature: 135 °C
Reaction time: 0.42 h

Procedure:
3-Hydroxy-4-methylbenzoic acid (1.07 g, 7.00 mmol), 3-isopropylbenzenamine (0.90 mL, 6.4 mmol), and DMAP (0.27 g, 2.2 mmol) were suspended in 25 mL dry toluene in a 2-neck flask with an attached Dean-Stark trap under N2. The mixture was stirred in a 135° C. oil bath and brought to a boil before PCl3 (0.28 mL, 3.2 mmol) was added dropwise by glass/Teflon syringe over 15 minutes. Heating was continued an additional 25 minutes. After cooling, the mixture was diluted with brine and ethyl acetate, and acidified with 1 NHC1. After extraction, the organic layer was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography (20-50% EtOAc/hexanes) to yield 3-hydroxy-N-(3-isopropylphenyl)-4-methylbenzamide as a white solid after concentration. MS m/z=268 [M−1]−. Calc'd for C17H19NO2: 269.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccccc1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2OC)n[nH]c1C
Temperature: 25 °C

Procedure:
A suspension of 10.0 g (0.0507 mole) of 4-(2-methoxyphenyl)-3-thiosemicarbazide and 8.35 g (0.0507 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred for ~16 hr at room temperature. Alcoholic hydrogen chloride (2N, 50 mL) was added, the mixture heated at reflux for 1.0 hr, and the solution filtered while hot to remove the precipitated sulfur. The filtrate was evaporated under reduced pressure, and the residue dissolved in hot ethanol, treated with charcoal and filtered through Celite®. The solution deposited 10.0 g of product, mp 162°-172° C. A similar recrystallization from absolute ethanol left 8.1 g, mp 155°-175° C. This product was dissolved in absolute ethanol, treated with charcoal, and filtered through Celite® 3 times. The filtrate deposited 4.3 g of product while standing for ~16 hr, mp 155.5°-159° C. which was a mixture of free base and hydrochloride salt. This last filtrate was left open to the atmosphere, and after approximately 50% of the solvent had evaporated, a solid precipitated and was collected by filtration: 1.4 g, mp 184°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)(=[O:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:27]1[S:31][C:30]([C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:33])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 48.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 5-acetylthiophene-2-carboxylic acid (85 mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (110 mg, 48%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)n1
Yield: 99.2 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (3 g, 16.22 mmol) in toluene (60 mL) was added ethylene glycol (4.97 g, 80.2 mmol) and p-toluenesulphonic acid (0.152 g, 0.8 mmol). The reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure to afford the crude which was dissolved in ethyl acetate and washed with water. The organic layers were washed with a brine solution, and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (3.7 g). The material was used for the next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].[CH2:29]([NH2:33])[CH:30]([NH2:32])[CH3:31]>>[NH2:32][CH:30]([CH3:31])[CH2:29][NH:33][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:25])[F:27])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(N)CN
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CC(N)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 140 °C
Yield: 85 %

Procedure:
A mixture of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (0.200 g, 0.502 mmol) and propane-1,2-diamine (2 mL) was heated in a sealed tube at 140° C. for 12 hours. The mixture was cooled and concentrated under high vacuum to remove excess amount of propane-1,2-diamine. The residue was purified by column chromatography to afford 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-aminopropyl)amide (0.188 g, 85%) as a white foam. 1H NMR (300 MHz, MeOH-d4) δ 7.92 (d, J=9.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.78-7.61 (m, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.30 (d, J=9.6 Hz, 1H), 4.00-3.82 (m, 4H), 3.72 (t, J=4.9 Hz, 2H), 3.45-3.23 (m, 5H), 1.10 (d, J=6.3 Hz, 3H). MS (ES+) m/z 437.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])O)[C:6]=2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.Br.[ClH:23].CCOCC>CO>[ClH:23].[CH2:16]([C:9]1[N:10]([CH:11]=[C:12]([CH3:14])[CH3:15])[C:6]2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CC(C)(C)O
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1C=C(C)C

Procedure:
4-Amino-2-butyl-α,α,6,7-tetramethyl-1H-imidazo[4,5-c]pyridine-1-ethanol (about 200 mg) was combined with concentrated hydrobromic acid (50 mL,) and heated at reflux overnight. The reaction mixture was concentrated under vacuum. The residue was taken up in methanol then diluted with ether. The resulting precipitate was collected then partitioned between methylene chloride and 10% sodium hydroxide. The organic layer was separated, dried over magnesium sulfate then concentrated to provide an oil. The oil was taken up in methanol then combined with 0.05 mL of concentrated hydrochloric acid followed by dilution with ether. The resulting precipitate was collected, rinsed with ether and dried to provide 60 mg of the desired product as a white solid, m.p. 205° C. (dec.). Analysis: Calculated for C16H24N4 +1.6 HCl: % C, 58.10; % H, 7.80; % N, 16.94; Found: % C, 57.95; % H, 7.87; % N, 16.89.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:26]=[N:25]1>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4([C:23]([F:37])([F:36])[F:22])[N:26]=[N:25]4)[CH:28]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(C2(C(F)(F)F)N=N2)c1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)c3cccc(C4(C(F)(F)F)N=N4)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 3-[3-(trifluoromethyl)-3H-diaziren-3-yl]benzoic acid (Preparation 197) to afford the title compound as a white solid in 36% yield, 23 mg.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1
Reactant: COCc1ccccc1B(O)O
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: COCc1ccccc1-c1ccc(OCc2nc(C(=O)O)cs2)cc1

Procedure:
2-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=356.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:7]>C(#N)C>[C:2]([NH:4][C:6](=[O:7])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)(=[O:3])[NH2:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Solvent: CC#N
Product: NC(=O)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1.20 g. (20 mmole) of urea and 2.02 g. (10 mmole) of p-nitrophenyl chloroformate in a dry flask under nitrogen were added 10 ml. of dry acetonitrile. The reaction mixture momentarily became clear and then a precipitate formed. The mixture was stirred for 18 hours at room temperature and the precipitate was filtered, washed with water and dried under vacuum. The dried product was triturated with ether and redried to yield 1.0 g. of crystalline product.
Reaction SMILES: C([O-])=O.[NH4+].C1(C[N:12]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13]2)C=CC=CC=1>[Pd].CO>[NH:12]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13]1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C1CCNC1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
0.704 g of 10% palladium on carbon (Pd/C) and then 11.5 g of ammonium formate are successively added at a temperature in the region of 20° C., under an argon atmosphere, to 5 g (22.8 mmol) of methyl (±)-1-(phenylmethyl)-3-pyrrolidinecarboxylate in solution in 100 cm3 of methanol. After stirring for 3 hours at the reflux temperature, the reaction mixture is filtered on Celite®. The Celite® is rinsed with 3 times 20 cm3 of methanol. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 2.5 g of methyl (±)-3-pyrrolidinecarboxylate in the form of a colorless oil.