Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([NH:2][NH2:3])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1)=[O:10]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(NN)c([N+](=O)[O-])c1
Reaction time: 0.75 h
Yield: 85 %

Procedure:
80 ml of hydrazine hydrate were poured into the suspension of 172.5 g of methyl 4-chloro-3-nitrobenzoate in 1600 ml of abs. ethanol under stirring, then the reaction mixture was refluxed while stirring for 45 minutes. The starting material dissolved and the product started to precipitate. After cooling down, the product was filtered by suction, washed with abs. ethanol and water successively until it became free from chloride ion. Thus, 4-methoxycarbonyl-2-nitrophenylhydrazine (143.6 g, 85%) was obtained as yellow crystals m.p.: 169°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:7][CH:6]=1)=[O:4].[Br:18]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccccc2C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccccc2CBr)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A 5 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a reflux condenser with a nitrogen inlet at the top, and a thermometer was charged with 53.42 g (0.204 mol) of 2'-methyl biphenyl-4-carboxylic acid methyl ester, 3.4 L carbon tetrachloride, 38.09 g (0.214 mol) of N-bromosuccinimide and 2.0 g of 2,2'-azobis(2-methylpropionitrile). The flask was degassed and flushed with nitrogen, the stirrer was started and the contents were refluxed for 5 hours. The reaction mixture was then cooled to room temperature, filtered and evaporated. The residual oil was purified by recrystallization from dichloromethane-hexane to afford 48.48 g (78%) of the product which had.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)c1cccc(Cl)c1
Product: N#Cc1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Prepared from 2-amino-5-bromobenzonitrile and 3-chlorophenyl boronic acid according to procedure A. Off-white solid: mp 118-119° C.; 1H-NMR (DMSO-d6) δ7.80 (d, 1H, J=2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0 Hz), 7.42 (t, 1H, J=7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.29 (br, 2H); Anal. Calc. For C13H9ClN2: C, 68.28; H, 3.97; N, 12.25. Found: C, 67.68; H, 4.06; N, 11.89.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:14]([CH:22]([S:24][CH2:25][C:26]([OH:28])=[O:27])[CH3:23])=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[C:14]([CH:22]([S:24]([CH2:25][C:26]([OH:28])=[O:27])=[O:9])[CH3:23])=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: Cc1cc2c(cc1C(C)SCC(=O)O)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(C)S(=O)CC(=O)O)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
1.7 g of 80% m-chloroperbenzoic acid was added to a solution of 2.0 g of [{1-(6-methyl-1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in 40 ml of chloroform under cooling with ice. The mixture was stirred at room temperature overnight and a crystalline insoluble matter was recovered by filtration and washed with ether to obtain 0.24 g of the intended compound (as a single diastereomer) in the form of white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]1=[O:12].[CH3:14][I:15]>C(#N)C>[I-:15].[CH3:1][N+:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]1=[O:12]
Reactant: CN(C)CCn1cc(Cl)cnc1=O
Reactant: CI
Solvent: CC#N
Product: C[N+](C)(C)CCn1cc(Cl)cnc1=O
Product: [I-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
1-(2-Dimethylaminoethyl)-5-chloropyrimid-2-one (0.004 mol) and methyl iodide (0.006 mol) were dissolved in acetonitrile (20 ml) and the reaction mixture was stirred at room temperature for 6 h. The precipitate was then collected, washed with ether and recrystallized by dissolving in boiling isopropanol (50 ml) to which water (in all 14 ml) was added dropwise, until dissolution was complete; yield 50%, m.p. 235° C. (decomp.). (Found: C, 31.34; H, 4.48. Calc. for C9H15ClIN3O: C, 31.46; H, 4.40).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21]Br)[CH:11]=3)=[CH:9][C:2]=12.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[N:23]1([CH2:21][CH2:20][CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:8]3[NH:7][C:3]4=[N:4][CH:5]=[CH:6][N:1]=[C:2]4[CH:9]=3)=[CH:11]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: BrCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylbromide [250 mg, Reference Example 4], morpholine (0.5 mL), potassium carbonate (100 mg) and potassium iodide (2 crystals) in ethyl methyl ketone was heated at reflux for 2 hours. The mixture was then allowed to cool to ambient temperature over 16 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give a yellow glass which was triturated with ethyl acetate and pentane to give the title compound (40 mg) as a yellow solid, m.p. 180–185° C. MS: 362 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.O.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>C(O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([O:20][CH2:44][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 62 %

Procedure:
Nα-Benzyloxycarbonyl (L) lysine (10 g; 35.7 mmol) in benzyl alcohol (30 cm3), toluene (30 cm3) and para toluene sulphonic acid (6.93 g) was heated under reflux. The water evolved from the reaction and from the p-toluene sulphonic acid monohydrate was collected azeotropically using a Dean and Stark apparatus. Refluxing was continued until the water was no longer collected. The reaction mixture was allowed to cool, when crystals formed. The crystals were filtered off and dried, yield=5 g. The proton magnetic resonance and infrared spectra showed this compound to be the p-toluene sulphonic acid salt of the starting material. The filtrate was poured into ether (300 cm3) forming an oil. The ether was decanted off and the oil washed with ether and dried under reduced pressure. The resultant oil slowly crystallised to afford 12 g (62%) of the title compound, ν (Nujol) 3370, 1735, 1692, 1040, 1015, 820, 745, 735, 700, 685 cm-1.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[OH:17][CH2:18][CH2:19]C1C=C(C=CC=1)C#N>>[OH:16][N:15]=[C:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:19][CH2:18][OH:17])[CH:12]=1)[NH2:1]
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: N#Cc1cccc(CCO)c1
Product: NC(=NO)c1cccc(CCO)c1

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-(2-hydroxy-ethyl)-benzonitrile (2 g, 13.59 mmol). Lyophilization of the reaction mixture gave the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 9.56 (s, 1H), 7.51-7.46 (m, 2H), 7.28-7.19 (m, 2H), 5.75 (bs, 2H), 4.64 (t, J=5.2 Hz, 1H), 3.63-3.57 (m, 2H), 2.71 (t, J=7.1 Hz, 2H). LC/MS (Method B): 181.1 (M+H)+.
Reaction SMILES: [Li]CCCC.[C:6]1([CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24](=[O:25])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH3:20])[C:14]=2[F:19])[CH2:27]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1Oc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.0 mL of 2.0 M n-BuLi (2.0 mL, 4.0 mmol) was added dropwise to a solution of 1-(o-tolyloxy)-2-fluorobenzene (0.7009 g, 3.5 mmol) in THF (15 mL); the internal temperature was maintained below −70° C. during the addition. A pale, yellow slurry resulted. Confirmation of proton abstraction was confirmed by quenching an aliquot on solid I2. A solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.1159 g, 4.1 mmol) in THF (15 mL) was added dropwise. The reaction was permitted to warm to rt and stirred at for 12 h. The reaction was quenched at 0° C. with satd aq NH4Cl and extracted with Et2O. The Et2O extracts were washed with aq NH4Cl and brine and dried over Na2SO4. Removal of the solvent left crude (3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)piperidine (1.79 g, ˜80% pure, quantitative) which was used directly without further purification.
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:4][C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: N#Cc1nccnc1Cl
Reactant: C=CCSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C=CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(allylthio)-1,3,4-thiadiazole-2-thiol (460 mg, 2.42 mmol), NaH (60% dispersion in mineral oil, 107 mg, 2.66 mmol), and 3-chloropyrazine-2-carbonitrile (338 mg, 2.42 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 85° C. under nitrogen atmosphere overnight.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:20]1[CH:21]=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1>N1C=CC=CC=1.[Cu]Br>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[CH:21]=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ncc(Br)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 0 °C

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (1.81 g, 8.33 mmol) was dissolved in pyridine (40 ml) and sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol) was added with stirring under argon at 0° C. The mixture was left to stir for 5 minutes. Copper (I) bromide (1.68 g, 11.7 mmol) was added and the mixture allowed to warm to room temperature over 30 minutes. 5-Bromo-2-pyrimidinecarbonitrile (D38) (2.30 g, 12.5 mmol) in pyridine (8 ml) was added and the mixture heated at 100° C. for 1 hour. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude product was purified by column chromatography, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (E177a); MS (ES+) m/e 321 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]#[N:12].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]#[N:12]
Reactant: COc1ccc(F)c(C#N)c1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 55 %

Procedure:
Synthesised from commercially available 2,6-difluoro-3-methoxybenzenecarbonitrile. Boron tribromide solution (1.0 M in CH2Cl2, 118.3 ml, 118.3 mmol, 2 equiv.) was added slowly, dropwise to stirred solution of 2,6-difluoro-3-methoxybenzenecarbonitrile (10 g, 59.1 mmol, 1 equiv.) in CH2Cl2 (270 ml), at room temperature The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water (600 ml), separated and extracted with CH2Cl2 (200 ml×2). The extracts were washed with water (250 ml×3) and dried (Na2SO4) to give a buff solid (7.15 g). This was dissolved in dichloromethane (250 ml) and extracted with dilute aqueous NaOH (6 g in 250 ml of water×2). The basic extracts were washed with CH2Cl2 (100 ml×3) and then acidified to pH 2 using concentrated HCl, extracted with CH2Cl2 (150 ml×4), washed with water (100 ml×2) and dried (Na2SO4) to give the desired compound as a cream solid (5.05 g). Yield 55%, mp 119-121° C., HPLC (Gemini C18, 50×4.6 mm): m/z 154 [M−H]−, Rt=3.07 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:18])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COC(C)(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (2.8 g, 24 mmol) and TEA (1.6 g, 16 mmol) in CH2Cl2 (15 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (1.9 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at rt for 4 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (2.1 g, 81%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.74 (m, 2H), 4.25 (t, 2H, J=7.5 Hz), 3.10 (s, 1H), 1.92 (t, 2H, J=7.5 Hz) 1.13 (s, 6H). Anal. Calcd. For C13H17F3O4S: C, 47.85; H, 5.25. Found: C, 47.95; H, 5.11.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(F)c1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(F)c1O
Reaction time: 0.25 h

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.2 g, 0.57 mmol) was added to a solution of 6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.2 g, 0.53 mmol) in MeOH (6 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (50 mg, 0.86 mmoL). After 15 hours the reaction mixture was quenched with 1N HCl and extracted with 10% MeOH in CH2Cl2. The combined organic layers were concentrated and recrystallized from EtOAc to give the product as a white soild (0.15 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.3 Hz, 3H), 1.43-1.72 (br m, 8H), 2.05-2.17 (m, 2H), 2.43 (m, 1H), 2.48-2.58 (m, 10H), 2.66 (d, J=17.4 Hz, 1H), 2.81 (d, J=17.4 Hz, 1H), 3.74 (d, J=16.2 Hz, 1H), 3.85 (d, J=16.2 Hz, 1H), 6.76 (s, 1H), 6.84 (d, J=11.6 Hz, 1H) 7.07 (s, 1H), 9.08 (s, 1H), 11.01 (s, 1H). MS: C28H32N4O4F (M+H+) 509.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:21][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1oc(-c2ccc(Cl)cc2)nc1CO
Reactant: O=S(Cl)Cl
Product: COC(=O)c1oc(-c2ccc(Cl)cc2)nc1CCl

Procedure:
100 mg (0.43 mmol) of the compound from Example 44A, together with 0.24 ml (3.24 mmol) of thionyl chloride, are stirred at RT for 8 h. The excess thionyl chloride is removed under reduced pressure and the residue is taken up in about 5 ml of ethyl acetate. The mixture is washed once with 2 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The product obtained is used without further purification in the subsequent reactions.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[S:33][CH:34]=[C:35]([C:37](O)=[O:38])[N:36]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:37]([C:35]3[N:36]=[C:32]([CH:29]4[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]4)[S:33][CH:34]=3)=[O:38])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 33.9 %

Procedure:
(S)-tert-butyl 4-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazol-2-yl)piperidine-1-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (400 mg, 1.534 mmol) and 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (479 mg, 1.534 mmol). The product was purified twice by Flash-chromatography. Yield 33.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.41 (s, 9H), 1.49-1.64 (m, 2H), 1.98-2.08 (m, 2H), 2.89 (bs, 2H), 3.15-3.27 (m, 1H), 3.96-4.09 (m, 2H), 4.29-4.52 (m, 3H), 6.96 (s, 1H), 7.84 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.06 (dd, 1H), 8.10 (s, 1H), 8.28 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](=[O:11])[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>CO.CCOC(C)=O.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH:4]1[CH2:5][CH:6]2[N:7]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:8](=[O:11])[O:9][CH:10]2[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a degassed solution of (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in MeOH and EtOAc (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.). The reaction was stirred under a hydrogen balloon overnight. Upon completion, the solution was filtered through a pad of Celite and the pad was washed with ethyl acetate. The filtrate was concentrated under vacuo to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate as the desired product as a yellow foam in 93% yield. LC/MS=348.1 (M+H), Rt=055 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Cl)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[S:13][C:12]=2[CH:33]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCCl)cc3)c(C3CCCC3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCC4)cc3)c(C3CCCC3)sc2c1

Procedure:
1 ml of pyrrolidine was added to 30 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-(2-chloroethoxy)phenyl]methanone, followed by reflux with heating for 1 hour. The mixture was concentrated under reduced pressure to distil off pyrrolidine, and the residue was purified by TLC (developing solvent, chloroform:methanol= 19:1) to obtain 28 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3-yl)[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CN1C(=O)CCC1.CO>ClCCl>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1Cl
Temperature: 140 °C
Reaction time: 60 h
Yield: 25.3 %

Procedure:
A pressure tube was charged with 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (600 mg, 2.01 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (863 mg, 4.03 mmol) and NMP (6 mL) to give a yellow suspension. The reaction mixture was stirred at 140° C. for 2.5 days. After cooling to room temperature, the NMP was distilled off using a Kugelrohr to afford a brown, viscous oil. This crude material was dissolved in dichloromethane and methanol and adsorbed onto silica gel. Purification by chromatography (spherical silica 20-45 m, 50 g, Versaflash column from Supelco, eluting from 100% dichloromethane to 84:15.2:0.8 dichloromethane/methanol/NH4OH), to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-chloro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (242.3 mg) as a brown solid. The product was then dissolved in dichloromethane (3 mL) and TFA (2.96 g, 2 mL, 26.0 mmol) was added. The mixture was stirred at room temperature for 2 h. The excess TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with a gradient of 0.05:0.95:99 NH4OH:methanol:dichloromethane up to 0.6:11.4:88 NH4OH:methanol:dichloromethane over 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (152 mg, 4%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (br. s., 1H), 8.42 (br. s., 1H), 8.05 (br. s., 1H), 7.59-7.80 (m, 2H), 6.78-6.99 (m, 2H), 3.18 (br. s., 1H), 2.57 (br. s., 4H), 1.21-1.42 (m, 2H), 1.20-1.81 (m, 8H), LC-MS 376 [M+H]+.