Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:12][C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(N(CC)CC)C.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.[Cu]I>[CH2:13]([C:3]1[C:4]2[S:8][C:7]3[CH:9]=[C:10]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:11][C:6]=3[C:5]=2[S:12][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCC
Reactant: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1cc2sc3c(CCCCCCCCCC)csc3c2s1
Temperature: 130 °C
Yield: 81.9 %

Procedure:
2-bromo-3-decanyldithieno[3,2-b:2′,3′-d]thiophene (92) (4.16 g, 0.01 mol) is mixed with 1-decyne (3.6 g, 0.026 mol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) and copper(I) iodide (0.19 g, 1.0 mmol) in triethylamine (80 mL). This mixture is bubbled with nitrogen for 5 minutes and then heated to 130° C. under argon for 16 hours. Triethylamine is evaporated and hexane (150 mL) is added. The mixture is filtered to remove solid salts and the organic layer is washed with 1M hydrochloric acid (50 mL) and brine (50 mL), then dried over MgSO4. The solvent is removed in vacuo, and the residue is purified by chromatography on silica gel eluting with hexane to yield the target compound (3.87 g, 93.0% yield). 1HNMR (CD2Cl2): δ 7.36 (d, 1H), 7.30 (d, 1H), 2.82 (t, 2H), 2.49 (t, 2H), 1.63-1.27 (m, 28H), 0.88 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[O:20].N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>O>[OH2:20].[OH2:20].[CH3:1][C:2]1([CH3:21])[C:19]2[C:5](=[CH:6][C:7]3[NH:11][C:10]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:9][C:8]=3[CH:18]=2)[NH:4][C:3]1=[S:29]
Reactant: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(=S)Nc2cc3[nH]c(-c4ccncc4)nc3cc21

Procedure:
A solution of 2.0 g (7.2 mmol) 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 35 ml. pyridine is heated for about 5 hours to 100° C. with 4 g. phosphorus pentasulphide (P4S10). Subsequently, the reaction mixture is decomposed with water, rendered alkaline and the desired product is extracted and purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). Yield: 1.7 g. (72% of theory); m.p. 205°-220° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(c2ccc(N)nc2)CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(c2cnc(N)c(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To an ice cold solution of 5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (50 mg, 0.26 mmol) in DCM (5 mL) was added NBS (50.9 mg, 0.28 mmol) in two portions. The reaction mixture was stirred at ambient temperature for 40 min. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered off, and concentrated to give 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol, 99% yield) as yellow color residue. LCMS (m/z): 271/273 (MH+), 0.41 min.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:28]5[CH:27]=[CH:26][C:25]([F:24])=[N:30][CH:29]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccc(F)nc3)ccc1-2
Yield: 50 %

Procedure:
Following the procedures for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 6-fluoropyridin-3-ylboronic acid to give 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-5-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (1.11 g, 50%). 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.47 (d, J=8.1, 1H), 8.38 (t, J=7.8, 1H), 8.12 (s, 1H), 7.61 (d, J=8.4, 1H), 7.49 (s, 1H), 7.30 (d, J=8.6, 1H), 5.84 (dd, J=13.2, 6.4, 1H), 4.43 (s, 2H), 3.49 (s, 2H), 1.57 (d, J=6.5, 6H). MS (ESI(+)): m/z 408.2 (M+H)
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[C:31]1([N:25]2[C:26]([C:27]([F:30])([F:28])[F:29])=[C:22]([C:20]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)=[O:21])[CH:23]=[N:24]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of methyl({4′-[({[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (284 mg, 0.557 mmol), prepared in the previous step, and 1 N NaOH (668 μL, 0.668 mmol) in 20 mL of THF and 10 mL of water was stirred at room temperature for 20 h (overnight). The reaction was acidified by the addition of 668 μL of 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (249 mg, 89%) as a white solid, MS (APCI) m/z 496 [M+H]+. Elemental Analysis for C26H20F3N3O4+0.38 H2O. Calc'd: C, 62.17; H, 4.17; N, 8.37Found: C, 61.91; H, 4.08; N, 8.00
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[C-]#N.[CH2:11]([C:13]([CH2:24][CH3:25])(O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12].[OH-].[Na+]>C(O)(=O)C>[CH2:11]([C:13]([NH2:2])([CH2:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12]
Reactant: CCC(O)(CC)Cc1ccc(OC)cc1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(N)(CC)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Powdered sodium cyanide (1.18 g, 24 mmol) was placed in a flask and covered with 5.5 mL of acetic acid. A mixture of sulfuric acid (3 mL) and acetic acid (2.75 mL) was cooled to 0° C. and then added to the cyanide suspension over a period of 3 minutes. The mixture was stirred for 30 minutes at room temperature, followed by the addition of 1,1-diethyl-2-(4-methoxyphenyl)ethanol (4.6 g, 22 mmol). The mixture was stirred overnight then poured into ice and sodium hydroxide. The product was extracted with ether, and the ether layer dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in 20% sodium hydroxide and refluxed overnight under nitrogen. The reaction was cooled, diluted with water, and extracted with ether. The ether layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (C-18 using 0.1% HCl acetonitrile as the elutant) to give 1.91 g of 1,1-diethyl-2-(4-methoxyphenyl)ethylamine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[O:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH:9]1[CH2:10][O:11][C:12](=[O:20])[CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCC1COC(=O)C1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1COC(=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 151.9 %

Procedure:
(5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl)carbamic acid tert-butyl ester (Description 4; 2.16 g, 7.4 mmol) was dissolved in dichloromethane (10 ml), cooled to 0° C., trifluoroacetic acid (1 ml) was added and the reaction was left to stand for 20 minutes to warm to room temperature. TLC showed the reaction to be incomplete so extra trifluoroacetic acid (1 ml) was added and the reaction was left for a further 30 minutes. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and saturate potassium carbonate solution. The aqueous layer was extracted with ethyl acetate (2×30 ml), the combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness. Purification was carried out by flash column chromatography on silica gel eluting in increasing concentrations of methanol in dichloromethane and 0.2% ammonia (1-10%) to afford the title compound (2.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[S:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccsc1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 429(M+)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>C(O)C>[O:19]1[CH2:20][CH2:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:17][CH2:18]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Diethyl malonate (32.0 g) was added to a solution of sodium ethoxide (1 equivalent) in ethanol and the solution was stirred for 30 min. 2-Bromoethylether (46.0 g) was then added and the mixture was stirred at reflux for 3 h. The mixture was then cooled, evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water and brine, then dried (MgSO4) and evaporated. The residue was then purified by flash column chromatography on silica gel, eluting with 4:1 hexanes/ether, to give the title compound (28.0 g) as colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH2:13]([C:12]1[NH:9][C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[Cl:1])[N:8]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Nc1ncnc(Cl)c1N
Reactant: CCCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCCc1nc2ncnc(Cl)c2[nH]1
Yield: 26.8 %

Procedure:
A mixture of 6-Chloro-4,5-diaminopyrimidine (0.289 g, 2 mmol) (from Step 1 of Example 12), trimethylorthovalerate (0.52 ml, 3 mmol) and p-TsOH (0.04 g) in 2-methoxyethanol (10 ml) was refluxed for 24 hours. The product was isolated and purified as described in Step 2 of Example 12 to give the crystalline titled compound (0.113 g, 23%). NMR (CDCl3): δ0.997 (t, J=9 Hz, 3H), 1.484 (m, 2H), 1.925 (m, 2H), 3.075 (m, 2H), 7.27 (s, 1H) and 8.723 (s, 1H). FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N, 26.60. Found: C, 51.34; H, 5.30, N, 26.46.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:4][CH2:3][CH:2]([NH2:1])[CH3:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 67.1 %

Procedure:
A mixture of (S)-(+) 2-amino-1-propanol (1.04 g, 13.85 mmol), tert butyldimethylsilyl chloride (2.09 g, 13.85 mmol) and triethylamine (2 ml, 1.05 eq) was stirred in DCM overnight ca 16 h. The reaction was diluted with DCM, washed with water, satd. NH4Cl, brine, dried and evaporated to an oil. Silica gel purification of the crude using 3% MeOH/CH2Cl2 as eluent provided 2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (1.76 g, 80%); 1H NMR (300 MHz, CDCl3) 0.0 (s, 6H), 0.82 (s, 9H), 0.99 (d, J=6.5 Hz, 3H), 2.22 (bs, 2H), 2.98 (bs, 1H), 3.30 (dd, J=10 Hz, J=17.0 Hz, 1H), 3.48 (dd, J=10.0 Hz, J=4.3 Hz, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[OH:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Reactant: CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred 0° C. solution of 1.0 g of 1-oxyl-4-amino-2,2,6,6-tetramethylpiperidine and 0.65 g of triethylamine in 10 mL of methylene chloride is added dropwise a solution of 0.95 g of octanoyl chloride in 5 mL of methylene chloride. After the addition is complete, the reaction mixture is allowed to warm to ambient temperature. After two more hours, the reaction mixture is washed with 1% aqueous sodium hydroxide and finally water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9](F)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+].C[O-].[C:21](O)(=[O:23])C>CO>[F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([O:23][CH3:21])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc2c(cc1F)OC(F)(F)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])OC(F)(F)O2
Temperature: 20 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2,2,5-Trifluoro-6-nitrobenzo[d][1,3]dioxole (2.5 g, 11 mmol) was dissolved in dry methanol (20 mL), treated with 30% sodium methoxide solution (3.1 g, 17 mmol), and stirred at 20° C. for 1 h. After excess methoxide was neutralized by addition of acetic acid, the volatiles were removed by rotary evaporation. The residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCO3 (10 mL), saturated NaCl (10 mL), dried (Na2SO4) and evaporated. The material was purified by chromatography on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound as a white solid (1.8 g, 70%): mp 84-85° C. 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.90 (s); EIMS m/z 233.
Reaction SMILES: [Cl:1][C:2]1([C:5]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=2)[CH2:4][CH2:3]1.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:16][C:9]1[C:5]([C:2]2([Cl:1])[CH2:4][CH2:3]2)=[N:6][N:7]([CH3:15])[C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Temperature: 80 °C

Procedure:
500 mg (2.19 mmol) of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate are dissolved in 10 ml of N,N-dimethylformamide p.a., and 438 mg (3.28 mmol)) of N-chlorosuccinimide are added. The reaction mixture is heated at 80° C. for 15. The cooled reaction solution is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is filtered through silica gel and eluted with ethyl acetate. This gives 517 mg (80%) of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate in a purity of 89%.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[CH3:11][O:12][C:13](Cl)=[O:14].[OH-].[Na+]>O>[CH3:11][O:12][C:13]([NH:10][C:8](=[NH:9])[O:7][CH3:6])=[O:14]
Reactant: COC(=N)N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N)NC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
246 g of O-methylisourea sulfate are dissolved in 300 ml of water and 163 ml of chloroformic acid methyl ester are added dropwise at 10° C., followed by 170 g of NaOH, dissolved in 510 ml of water. The mixture is stirred at room temperature for a further 3 hours. The reaction solution is then extracted with ethyl acetate and this extract is dried with anhydrous sodium sulfate. Evaporation under reduced pressure at a maximum bath temperature of 40° C. gives the N-methoxycarbonyl-O-methylisourea as an oil, which gradually solidifies to form crystals with a melting point of 40° C. Yield 150 g.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>COCCOCCOC>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH2:18][CH2:19]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)o1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: FC(F)(F)c1cccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5-Phenyl-2-furoyl)-4-(3-trifluoromethylphenyl)-piperazine (6.0 g, 0.015 mole) and sodium borohydride (1.28 g, 0.034 mole) were stirred in diglyme (25 ml), under nitrogen, and redistilled boron trifluoride etherate (6 ml, 0.045 mole) in diglyme (20 ml) added dropwise with continuous stirring. The resultant clear solution was stirred at room temperature for 3 hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 ml), followed by 5NHCl (20 ml) and the mixture heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4N NaOH) and extracted via diethyl ether. The dried ether extract (MgSO4) was evaporated to give an oil which failed to crystallise. The product was converted to the hydrochloride and then reconverted to the free base as in Example 40. The base was obtained as a mobile oil which on very strong cooling crystallised, m.p. 56° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2/[C:7](=[N:10]\O)/[CH2:8][CH2:9][C:2]=12.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([NH2:10])[CH2:8][CH2:9][C:2]=12
Reactant: O/N=C1/CCc2ncccc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1CCc2ncccc21
Temperature: -40 °C
Yield: 68 %

Procedure:
To a solution of (5Z)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one oxime (320 mg) in methanol (20 ml) under N2 was added nickel chloride hexahydrate. The reaction mixture was cooled to −40° C. and sodium borohydride (817 mg) was slowly added over 30 min. The reaction mixture was warmed to ambient temperature for 1 h and silica gel was added. The reaction mixture was concentrated. MPLC chromatography was run using a biotage 25S column with 5–8% methanol/methylene chloride with 0.5% ammonium hydroxide to provide the title compound as an oil (197 mg, 68%): 1H NMR (400 MHz, CDCl3) δ 8.43, 7.66, 7.28, 7.15, 4.42, 3.13–3.00, 2.97–2.91, 2.63–2.55, 1.81–1.72.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>>[NH:17]1[C:16]([NH:15][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:10])=[N:20][N:19]=[N:18]1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cccc(Cl)n1
Yield: 25.9 %

Procedure:
0.46 g of 6-chloro-2-pyridinecarboxylic acid, 15 ml of thionyl chloride and 0.29 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.17 g of N-(5-tetrazolyl)-6-chloro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)=[CH:11][C:12]=1[NH2:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H](c2ccc(OCc3ccccc3)c(N)c2)CC1

Procedure:
116.5 g of 4-(trans-4-n-propylcyclohexyl)-2-amino-phenol, 80 g of potassium carbonate and 110 g of benzyl bromide are heated to 100° for 10 seconds in 500 ml of N,N-dimethyl-formamide. Subsequently, the reaction mixture is poured into 1 l of water. From the mixture obtained, the 4-(trans-4-n-propylcyclohexyl)-2-aminophenyl benzyl ether formed is extracted with dichloromethane and, after distilling off of the extraction agent, is recrystallized from isopropanol; yield 120 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 99.9 %

Procedure:
Methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (960 mg, 3.01 mmol) and palladium, 10% on carbon (96 mg, 0.09 mmol) in ethanol (10 ml) and ethyl acetate (40.0 ml) were stirred under an atmosphere of hydrogen at atmospheric pressure and ambient temperature for 18 h. The reaction mixture was filtered through celite, washing with methanol, ethyl acetate and dichloromethane and concentrated under reduced pressure to give methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-5-carboxylate (966 mg, 100%) as a yellow oil, which crystallised on standing. This was used directly with no further purification.