Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([C:15]#[N:16])=[CH:14][C:5]2=1.C[Li].[O:19]1[CH:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH:21]([OH:19])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]1[CH:11]=[N:12][C:13]([C:15]#[N:16])=[CH:14][C:5]2=1
Reactant: N#Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Li]C
Product: N#Cc1cc2c3cc(Br)ccc3n(CC(O)COc3ccccc3)c2cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
6-bromo-9H-pyrido[3,4-b]indole-3-carbonitrile (21.3 mg, 0.785 mmol) was added to a flask and purged with nitrogen. THF was added and the solution was cooled to −78° C. Methyl lithium (1.6 M in Et2O) (1.1 eq) was added and was stirred for 30 minutes. 1,2-epoxy-3-phenoxypropane (0.011 mL, 0.824 mmol) was added with gradual warming to 45° C. Upon completion the reaction was quenched with 1 N HCl and extracted 3× with EtOAc. The organic layer was washed with H2O, brine, and dried over Na2SO4. The crude mixture was purified on SiO2 (0 to 50% EtOAc/hexanes to afford the desired product in 90% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (2 g) and β-alanine ethyl ester hydrochloride (0.84 g) and 1-hydroxybenzotriazole (0.74 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester as a colorless oil (2.54 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C>[C:15]([N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][CH3:2])=[CH:5][C:6]=2[CH2:12][CH2:11]1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)CCNCC2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CCN(C(C)=O)CC2
Reaction time: 16 h

Procedure:
A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (4.3 g, 0.02 m) and sodium acetate (3.3 g, 0.04 m) in acetic anhydride (13 ml) was refluxed and stirred for 16 hours, concentrated in vacuo and partitioned between methylene chloride and water. The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 89°-90°.
Reaction SMILES: [C:1](=[O:46])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:2][C@H:3]1[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5][C@@H:4]1[CH2:29][O:30][Si](C(C)(C)C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:62]([C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:71])[C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65]>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:73]([O:72][C:70]([NH:62][C@@H:63]([CH:64]([CH3:66])[CH3:65])[C:67]([O:30][CH2:29][C@@H:4]1[C@@H:3]([O:2][C:1]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:7][C@H:6]([N:8]2[CH:13]=[C:12]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[O:16][C:11]3=[N:10][C:9]2=[O:28])[O:5]1)=[O:68])=[O:71])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)OCc5ccccc5)[C@@H](COC(=O)[C@@H](NC(=O)OCc5ccccc5)C(C)C)O4)c(=O)nc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL flask was added 53 mg (0.1 mmol) of (2R,3S,5R)-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3 (2H)-yl)-2-((tert-butyldimethylsilyloxy)methyl)-tetrahydrofuran-3-yl benzyl carbonate, 12 mg (0.1 mmol) of DMAP, 31 mg (0.15 mmol) of DCC, 30 mg (0.12 mmol) of Cbz-Val-OH, and 5 mL of THF. The mixture was stirred at rt for 2 h.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH2:16][NH2:17].COCC(O)C>>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH:14][CH2:15][CH2:16][NH2:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1cc(Cl)c2ccccc2n1
Reactant: NCCN
Solvent: COCC(C)O
Product: COc1cc(NCCN)c2ccccc2n1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
4-Chloro-2-methoxy-quinoline (484 mg, 2.5 mmol) and 1,2-diaminoethan (751 mg, 12.5 mmol) were mixed with 1-methoxy-2-propanol and stirred at 110° C. for 24 hours. The mixture was evaporated to dryness and the residue was purified by column chromatography (pre-packed silica column, gradient of ethyl acetate/methanol each containing 1% triethylamine). 0.324 g were obtained (1.49 mmol; 60%). MS (APCI) m/z=218.0 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].[NH3:16]>O1CCCC1>[NH2:16][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3]
Reactant: N
Reactant: CON=C(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CON=C(Cl)c1ccccc1S(N)(=O)=O
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the oil prepared in Example 3 in 100 ml of tetrahydrofuran, cooled at -30° C. with external cooling, was added dropwise 1.7 ml of ammonia. After stirring at -30° C. for about 15 minutes, the suspension was purged with N2 to remove excess ammonia, then evaporated at less than 30° C. under vacuum. After adding ice-water to the residue the suspension was extracted with methylene chloride, dried (MgSO4) and evaporated under vacuum. The residue was triturated with hexane to yield 2.5 g of the subject compound as a crude solid, m.p. 155° to 158° C., NMR(CDCl3 +DMSO): ppm 4.2(s, 3H, OCH3) 6.6 (bs, 2H, NH2), 7.8 (m, 4H, Ar).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>O1CCOCC1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH3:6])[C:11]=1[C:12]#[N:13]
Reactant: CC[C@H](N)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](N)COc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.01 g (51.3 mmol) (S)-2-amino-1-butanol are dissolved in 30 mL 1,4-dioxane, combined with 2.10 g (52.5 mmol) sodium hydride and stirred for 30 min at ambient temperature. To this reaction mixture are added 5.00 g (36.7 mmol) 2-amino-6-fluorobenzonitrile and the mixture is stirred for 24 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant is dichloromethane to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[OH:36])(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1([CH3:71])[CH:61]=[CH:60][C:59]([S:62]([O:65][CH2:66][CH2:67][CH:68]([CH3:70])O)(=[O:64])=[O:63])=[CH:58][CH:57]=1>O1CCCC1>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH:68]([CH3:70])[CH2:67][CH2:66][O:65][S:62]([C:59]1[CH:58]=[CH:57][C:56]([CH3:71])=[CH:61][CH:60]=1)(=[O:63])=[O:64])(=[O:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC(C)CCOS(=O)(=O)c2ccc(C)cc2)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reaction time: 4 h
Yield: 36.9 %

Procedure:
A solution of diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)benzothiazoline (2.56 g, 7.62 mmol), triphenylphosphine (2.00 g, 7.61 mmol) and 3-p-toluenesulfonyloxy-1-methylpropanol (1.86 g, 7.61 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for four hours. The reaction mixture was concentrated, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=4/1) to give 1.58 g (37%) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]1(CC(C2C=CC=CN=2)O)C[CH2:11]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: OC(CC1CC1)c1ccccn1
Reactant: Cc1cccc(C=O)n1
Product: CCC(O)c1cccc(C)n1

Procedure:
The title compound was prepared from 6-methyl-2-pyridinecarboxaldehyde (purchased from Tokyo Chemical Industry Co. Ltd.) using a procedure similar to the one described above for the synthesis of 2-cyclopropyl-1-(pyridin-2-yl)ethanol (Example 232, Step A). Mass Spectrum (ESI) m/z=151.4 (M+1).
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH2:55])=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH2:38][CH2:37]1.[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[C:62]1[C:63]([C:68](O)=[O:69])=[N:64][CH:65]=[CH:66][CH:67]=1>>[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH:55][C:68]([C:63]3[C:62]([C:57]4[N:56]=[CH:61][CH:60]=[CH:59][N:58]=4)=[CH:67][CH:66]=[CH:65][N:64]=3)=[O:69])=[N:41][CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[N:44]=2)[CH2:37][CH2:38]1
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 48; 105 mg, 0.33 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 79 mg, 0.39 mmol) except after work-up, the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM, then methanol and 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20](F)[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.N([O-])=[O:35].[Na+]>CN(C)C=O>[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=N[O-]
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c(=O)n1-c1cccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(O)c2c(=O)n1-c1cccnc1
Temperature: 220 °C
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
A mixture of 8-fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (2a, 70.0 mg, 0.157 mmol), sodium nitrite (NaNO2, 77.0 mg, 1.12 mmol) in N,N-dimethylformamide (0.7 mL) was heated under microwave irradiation at 220° C. for 30 min. The obtained dark solution was quenched with 3M aq. HCl (5 ml), stirred for 20 min and partitioned with ethyl acetate (3×5 mL). Each organic solution was washed with 1M HCl (3×2 mL). The combined aq. solution was basified with NaHCO3 (pH=7) and extracted with ethyl acetate. The combined organic extracts were absorbed on 1 g SiO2 and flash chromatographed on 20 g silica gel with gradient heptane-ethyl acetate. The product came out with 75% ethyl acetate and only pure fractions were evaporated to give 7.1 mg of a brown residue, yield 10%. LC-MS (m/z) 444.6 (MH+); tR=1.26. 1H NMR (500 MHz, 70° C., DMSO-d6): 0.48 & 0.59 (two br. s, 2×2H, two CH2 of Cp), 1.27 (br. s, 1H, CH of Cp), 1.91 (br. s, 3H, Me), 4.51 (t, J=8.5 Hz, 1H, CHNH), 6.87 (overlapping d, J=8.1 Hz, 1H), 6.9 (overlapping br. s, 1H), 7.06 (br. T, J=8.3 Hz, 1H), 7.26 (d, J=10.5 Hz, 1H), 7.3 (d, J=7.6 Hz, 1H), 7.40 (q, J=7.2 Hz, 1H), 7.59-7.66 (br. m, 2H), 7.86 (br. m, 1H), 8.58 (s, 1H), 8.72 (s, 1H), 8.93 (br. d, J=7.8 Hz, NHCO), 12.46 (s, 1H, OH).
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]I)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-:29])(=[S:28])[CH3:27].[K+]>CC(C)=O>[C:26]([S:28][CH2:24][CH2:23][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])(=[O:29])[CH3:27]
Reactant: CC([O-])=S
Reactant: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(CCSC(C)=O)(Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(a) A mixture of 5.2 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 1.31 g of potassium thioacetate in 150 ml of acetone was stirred at room temperature for 8 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Trituration with diethyl ether gave 3.5 g of diasteremoer B in the form of a white solid having a melting point of 161°-162° C. (from ethylacetate).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=O)(C)(C)C.[S:16](N)(N)(=[O:18])=[O:17]>N1C=CC=CC=1>[S:16]1(=[O:18])(=[O:17])[N:11]2[CH:10]([CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:14][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCNC(CN)C1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)NCC2CNCCN21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-aminomethyl-piperazine-1-carboxylic acid tert-butyl ester (CAS number: 1376099-80-7, Bepharm) (215 mg, 1.0 mmol) in 2 mL of pyridine was added sulfamide (1.5 mmol). The reaction mixture was heated to 150° C. for 6 hours under microwave. The solvent was removed in vacuo, and the residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. The reaction mixture was stirred for 1 hour, and the solvent was removed in vacuo to give the crude Compound P which was used directly without further purification. LC/MS: calc'd 178 (MH+), measured 178 (MH+).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](=O)[CH3:5].[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#N.C1C[O:19]CC1>>[CH3:5][C:4]1[CH:3]=[C:2]([CH3:7])[NH:1][C:8](=[O:19])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC#N
Reactant: C1CCOC1
Reactant: CC(=O)/C=C(/C)N
Product: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Reaction time: 5 h
Yield: 19.9 %

Procedure:
A solution of (Z)-4-aminopent-3-en-2-one (20.0 g, 0.2 mol) in dry THF (20 mL) is added to a solution of ethyl cyanoacetate (22.6 g, 0.2 mol) and TEA (20.2 g, 0.2 mol) in dry THF (200 mL). The reaction mixture is heated at reflux for 56 hours and then concentrated. The residue is kept standing at RT for 5 hours and the precipitate is filtered and washed with EtOAc to afford the title compound (7.3 g, 19.9% yield). MS (m/z): 196.0 (M+H).
Reaction SMILES: Cl.[CH:2]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:5][CH2:4][CH2:3]1.[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.Cl>O1CCOCC1>[CH:2]1([C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[CH2:9][C@@H:10]([C:12]([O:14][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:13])[NH2:11])[CH2:3][CH2:4][CH2:5]1
Reactant: N[C@@H](Cc1cccc(C2CCC2)c1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C2CCC2)c1
Yield: 81 %

Procedure:
According to example 54, 0.65 g of 3-cyclobutyl-L-phenylalanine HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2SO4. Work-up in the usual manner followed by acidification of the free amine with ethereal HCl afforded 0.64 g (81%) of tert-butyl 3-cyclobutyl-L-phenylalaninate.HCl as a white powder, m.p. 173-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[N:23]#[C:24]Br>CCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:24]#[N:23])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reaction time: 2 h

Procedure:
A suspension of 7-Chloro-4-(piperazin-1-yl)quinoline (496 mg, 2.0 mmol) and NaHCO3 (504 mg, 6.0 mmol) in EtOH is treated with cyanogen bromide (5 M in MeCN, 440 μL, 2.2 mmol) and stirred at room temp. for 2 h. The solvent is removed, and the residue suspended in CH2Cl2 and filtered. The filtrate is concentrated, and the residue is purified by column chromatography with hexane-EtOAc giving 221 mg of the product as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
A solution of acryloyl chloride (20 μL, 0.25 mmol) was added dropwise to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 150, 180 mg, 0.42 mmol) and triethylamine (73 lilt, 0.53 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 0.25 h. The reaction was judged to be incomplete so further acryloyl chloride (10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0° C. for a further 15 minutes. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH. This solution was washed with sat. NaHCO3 (2 mL), dried (MgSO4) and filtered through a 1 g silica pad, eluting with 4:1 CH2Cl2—CH3OH. Eluent that contained desired product was concentrated in vacuo. Purification by FCC, eluting with 5-20% CH3OH in CH2Cl2 gave the title compound (31 mg, 14%) as a cream crystalline solid; 1H NMR: 2.33 (3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70 (2H, m), 6.17 (1H, m), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32 (1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, d), 8.51 (1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES+ MH+ 482.
Reaction SMILES: [CH:1]1([CH2:10][C:11](Cl)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[CH2:21][S:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].C1(CC(Cl)=O)C2C(=CC=CC=2)CC1>>[CH:1]1([CH2:10][C:11]([CH:19]2[S:20][CH2:21][NH:14][C@@H:15]2[C:16]([OH:18])=[O:17])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)CC1C=Cc2ccccc21
Agent: O=C(Cl)CC1CCc2ccccc21
Product: O=C(CC1C=Cc2ccccc21)C1SCN[C@@H]1C(=O)O
Yield: 44 %

Procedure:
Colorless crystals of 3-(2-indenylacetyl)-L-thioproline were prepared in the same manner as Reference Example 10, except that 2-indenylacetyl chloride and L-thioproline were used instead of 2-indanylacetyl chloride and L-piperidin-2-ylcarboxylic acid, respectively (yield: 44%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH2:28][CH2:27][CH2:26][CH:25](Br)[C:24]=1O)=[O:22])[CH3:19]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:18]([O:20][C:21]([CH:23]1[C:24]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]=2[CH2:26][CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: c1ccc(COCCNc2ccccc2)cc1
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (8.0 g, 26 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4; prepared according to Example 1(d)) (3.2 g, 13 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (30 mL) and dry zinc chloride (10.6 g, 78 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 2 N HCl (100 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (2.5-40% B, 17 CV, 330 g, 100 mL/min) to give 3.49 g (72%) of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (25) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC14.2, 20.5, 21.8, 26.5, 38.6, 42.9, 60.4, 68.7, 73.2, 106.4, 108.8, 118.7, 120.7, 127.4, 127.5, 128.3, 136.2, 136.9, 137.8, 175.0.