Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC[C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1.[F:38][CH2:39][CH2:40][CH2:41][CH2:42]C#C.FCC#C>>[F:38][CH2:39][CH2:40][CH2:41][CH2:42][C:3]1[N:4]=[N:5][N:6]([CH2:8][N:9]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[C:12](=[O:13])[C:10]2=[O:11])[CH:7]=1
Reactant: C#CCCCCF
Reactant: O=C1C(=O)N(Cn2cc(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Agent: C#CCF
Product: O=C1C(=O)N(Cn2cc(CCCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
is prepared according for the procedure for compound 6, with the exception that 6-fluorohex-1-yne is used in place of the (3-fluoroprop-1-yne). For the preparation of [18F]9, 6-[18F]fluorohex-1-yne is used in place of 3-fluoroprop-1-yne.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:22]([C:8]1[C:7]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)[N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc2cc(OS(=O)(=O)C(F)(F)F)c(Cc3ccccc3)nc2c1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
A mixture of 220 mg of 2-benzyl-7-ethoxycarbonyl-3-quinolyl Trifluoromethane sulfonate, 83 mg of 3-ethynyl-3-quinuclidinol, 116 mg of tetrakis(triphenylphosphine)palladium(0), 19 mg of cuprous iodide, 209 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was stirred at room temperature for 45 minutes in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 220 mg of the target compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][N:16]1[CH2:17][CH2:18][CH:14]([C:6]2[NH:7][C:8](=[O:13])[C:9]3[C:4]([CH:5]=2)=[C:3]([CH3:2])[CH:12]=[CH:11][CH:10]=3)[CH2:15]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Reactant: OCCCBr
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCO)C3)cc12

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (501 mg) and 3-bromo-1-propanol (991 μl), 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (216 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[N:20]12[CH2:30][CH2:29][CH2:28][N:27]=[C:26]1[CH2:25]CCCC2.N1CCC(CN)C1>C(#N)C>[NH2:20][CH2:30][CH:29]1[CH2:25][CH2:26][N:27]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:28]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CCC2=NCCCN2CC1
Agent: NCC1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 0.50 g (1.84 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml of acetonitrile, 0.28 g (1.84 mmole) of 1,8-diazabicyclo [5.4.0]undec-7-ene and 0.19 g (1.94 mmole) of 3-pyrrolidinemethanamine was refluxed for one hour; then stirred at room temperature overnight. The reaction was filtered and the precipitate washed with ethyl ether to give 0.56 g of 7-[3-(aminomethyl)-1-pyrrolidinyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 219°-221° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[CH2:35][CH2:34]2)=[CH:29][C:28]=1[O:46][CH3:47].FC(F)(F)C(O)=O>COCC(O)C>[F:44][C:41]([F:42])([F:43])[C@@H:40]([OH:45])[CH2:39][N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[C:28]([O:46][CH3:47])[CH:29]=2)[CH2:38][CH2:37]1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1N
Agent: CS(=O)(=O)O
Solvent: COCC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 135 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (50.00 mg, 0.174 mmol), methanesulfonic acid (0.034 mL, 0.52 mmol) and (S)-3-[4-(4-amino-3-methoxy-phenyl)-piperidin-1-yl]-1,1,1-trifluoro-propan-2-ol (109 mg, 0.342 mmol) were combined in 1-methoxy-2-propanol (1.02 mL) in a capped tube and the reaction was stirred at 135° C. for 48 h. The product was isolated by reverse phase preparative hplc (Gilson) followed by neutralization of the trifluoroacetic acid salt to afford (S)-1,1,1-trifluoro-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propan-2-ol as a brown solid (17 mg, 18%). MP: 77-94° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.44 (m, 2H), 7.14 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.02 (4.4 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.71 (m, 2H), 4.08 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.02 (m, 2H), 2.67 (m, 2H), 2.52 (m, 2H), 2.23 (m, 1H), 1.77 (m, 3H); LC/MS (ESI+): 542.3 (M+H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH:1]1([O:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2cccc(OC3CCCCC3)n2n1
Agent: Cl
Product: O=C(Nc1nc2cccc(OC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure and work up described for intermediate B1 but starting from 5-(cyclohexyloxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A11), 268 mg; 1.15 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (247 mg; 1.38 mmol; 1.2 eq.) as an off-white foam (230 mg, 59%). HPLC, Rt: 2.36 min. (purity 94.7%). LC/MS, M−(ESI): 336.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34](CN)[CH:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(Oc2cc(CN)ccn2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)ccn2)CC1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.388 g, 1.20 mmol) and 1-{2-[(1-methylpiperidin-4-yl)oxy]pyridin-4-yl}methanamine (0.242 g, 1.09 mmol, from step b above) were mixed with 1.0 g of phenol and heated to 120° C. for 2 h. The mixture was purified by preparative HPLC (Kromasil C8-50×250 mm, CH3CN/0, 1 M NH4OAc 5/95-50/50 and CH3CN/0, 2% HOAc 5/95-50/50). The product was freeze dried from water. Yield: 0.154 g (27%). 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.09 (d, 1H), 7.94 (s, 1H), 7.90 (m, 2H), 7.58 (m, 2H), 6.88 (m, 1H), 6.60 (bs, 1H), 5.20 (s, 2H), 4.95 (m, 1H), 2.60 (m, 2H), 2.15 (s, 3H), 2.12 (m, 2H), 1.92 (m, 2H), 1.62 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 163.7, 158.6, 156.8, 150.6, 149.4, 147.9, 135.1, 131.9, 130.0, 128.7, 122.5, 122.4, 116.1, 109.7, 53.4, 48.5, 46.5, 31.3. MS (ESI+) 467/469 (M+1H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([OH:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:8])[CH3:7].N1C=CC=CC=1>C(Cl)Cl>[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([O:36][C:1](=[O:3])[CH3:2])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:7])[CH3:8]
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 22 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Acetyl chloride (9 μL, 0.125 mmol) was added to a solution of (3S,6S,7R,8R)-8-(cyclohexylmethyl)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (50 mg, 0.100 mmol) and pyridine (40 μL, 0.480 mmol) in CH2Cl2 (1 mL), and the reaction was stirred at ambient temperature (about 22° C.) overnight. The solution was loaded directly onto a pre-packed SiO2 column for purification by column chromatography (0→30% EtOAc/CH2Cl2) to afford the title compound (28 mg, 52%) as a white solid: mp 164-170° C.; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=7.5 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 5.47 (br s, 1H), 5.25-5.11 (m, 1H), 5.03 (t, J=9.9 Hz, 1H), 4.97-4.84 (m, 1H), 3.92 (s, 3H), 3.72 (br s, 1H), 2.69 (dd, J=16.8, 7.0 Hz, 1H), 2.60 (sept, J=14.0, 7.0 Hz, 1H), 2.40 (s, 3H), 1.83-1.54 (m, 6H), 1.36-1.02 (m, 14H), 0.94-0.67 (m, 2H); HRMS-ESI (m/z): calcd for C28H38N2O10, 562.2526; found, 562.2516.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=O)[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[CH:29]2[CH2:30][CH:31]([NH2:32])[CH:27]([CH2:28]2)[CH2:26]1>>[CH:27]12[CH2:28][CH:29]([CH2:25][CH2:26]1)[CH2:30][CH:31]2[NH:32][CH2:23][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:8]=1[OH:22]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: NC1CC2CCC1C2
Product: CC(C)(C)c1cc(CNC2CC3CCC2C3)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
3-((Bicyclo[2.2.1]heptan-2-ylamino)methyl)-5-(tert-butyl)-4′-(trifluoromethoxy)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-2-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carbaldehyde (Intermediate 5) and exo-2-aminonorbornane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(O)CCCCC.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Solvent: Clc1ccccc1Cl
Product: c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 8-aminoquinoline (1.5 g), bis-(2-chloroethyl)amine hydrochloride (2.04 g), o-dichlorobenzene (4.5 mL) and n-hexanol (0.45 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the mixture was treated with 2 N NaOH (10 mL) and extracted with CH2Cl2 (3×20 mL). The purification was carried out by flash chromatography (CH2Cl2-2 N methanolic NH3) 97:3 to give 0.48 g (22%) of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:6])(=[S:5])[CH3:4].[C:7]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH2:8][CH3:9]>CO>[C:7]([NH:11][C:12](=[O:15])[CH2:13][S:5][C:3](=[O:6])[CH3:4])(=[O:10])[CH2:8][CH3:9]
Reactant: CC(O)=S
Reactant: CCC(=O)NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NC(=O)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nitrogen was bubbled through 4.0 g. (0.1 mole) of sodium hydroxide in 200 ml. of methanol and to this there was added 7.1 ml. (0.1 mole) of thioacetic acid and then 16.0 g. (0.1 mole) of N-propionyl-2-chloroacetamide. The reaction mixture was stirred at ambient temperature for 2 hours and then stripped in vacuo and filtered. The product was dissolved in boiling water, treated with charcoal, filtered and dried in vacuo. A yield of 6.0 g. of white crystalline product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: Cc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP12), chlorination of 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (389 mg; 0.727 mmol) and purification by FC (DCM/MeOH=20/1) gave the product 1-chloro-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (33 mg; 0.074 mmol). LC-MS: tR=1.02 min.; [M+H]+=444.44 g/mol.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:13][C:14]1[NH:18][C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)=[N:16][C:15]=1[C:30](=[O:32])[NH2:31].C(=O)([O-])O.[Na+].O>C1COCC1>[C:30]([C:15]1[N:16]=[C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)[NH:18][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:32])[NH2:31]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(Cc2nc(C(N)=O)c(N)[nH]2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)OCC)o3)nc2C(N)=O)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
4-Propylbenzoyl chloride (2 ml; 11.9 mM) are added dropwise to 3 g (10.8 mM) of ethyl 5-(5-amino-4-carbamoyl-1H-imidazol-2-ylmethyl)furan-2-carboxylate and 1.8 g of sodium hydrogen carbonate (21.6 mM) in 15 ml of THF. The reaction medium is then stirred at 20° C. for 20 hours. After addition of water, a solid precipitate is formed, which is isolated and purified by chromatography on silica, first using a dichloromethane/acetone mixture (90/10) as eluent, and then a dichloromethane/methanol mixture (90/10) to give 2.9 g of ethyl 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylate in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11](NCCC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH2:9][CH2:10][CH2:11][NH:12][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCCNC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc(S(=O)(=O)N2C(CCCNS(C)(=O)=O)CCC2c2ccc(F)cc2)cc1

Procedure:
Reaction of (2RS,5RS)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propylamine with methanesulfonyl chloride according to the general method of example 1d yielded the title compound as a white solid, m.p. 123° C. and MS: m/e=455.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](O)[CH:32]=1>CN(C)C=O>[N+:37]([C:36]1[CH:31]=[CH:32][C:33]([O:14][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:34][CH:35]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Nα -t-Butoxycarbonyl-D-valine p-nitrophenyl ester is prepared from 5 g., 24 mmol, of Nα -t-butoxycarbonyl-D-valine, 4.8 g., 24 mmol, of dicyclohexylcarbodiimide and 3.4 g., 24 mmol, of p-nitrophenol dissolved in 25 ml. of dimethylformamide and the solution let stand at room temperature overnight. The solids are separated by filtration and the filtrate evaporated to dryness under reduced pressure. The residual oil is purified by chromatography on silica gel in methanol-benzene (5:95); 5 g.; [α]D23 +21° (c 1.0, methanol); ultraviolet in methanol λmax 270 E11 204.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[N:31]1([C:37](=[O:39])[CH3:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:37]([N:31]1[CH2:36][CH2:35][N:34]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][C:4]=3[C:27]([F:30])([F:29])[F:28])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH2:33][CH2:32]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Product: CC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-Acetyl-piperazin-1-yl)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-piperazin-1-yl-ethanone following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1ccccn1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-pyridin-2-ylethanone (6.27 g 29 mmol) in methanol (100 ml) was added a solution of hydroxylamine hydrochloride (9.6 g 130 mmol) and sodium acetate (15.6 g) in water (80 ml) and the reaction was stirred at room temperature for 24 hours. The resulting precipitate was filtered off and dried to give the title compound as a white solid (5.83 g 87%). (M-H2O)H+: 213; NMR: (CDCl3): δ 4.42 (2H, s) 7.00 (2H, t) 7.14 (1H, m) 7.28 (1H, d) 7.59 (1H, dt) 7.72 (2H, m) 8.55 (1H, m) 8.96 (1H, br).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C#N)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 80.4 %

Procedure:
The compound methyl 3-cyano-5-ethylbenzoate (270 mg, 1.42 mmol) was dissolved in THF—H2O (7:3 v/v, 10 mL), solution was cooled to 0° C. and LiOH (59 mg, 1.42 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred for 3 h (monitored by TLC; petroleum ether/EtOAc 1:1). Solvent THF was removed under reduced pressure and the aqueous layer was washed with EtOAc to remove the non-polar impurities. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCl. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3-cyano-5-ethylbenzoic acid (200 mg, yield 80%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.23 (m, 1H), 8.17 (m, 1H), 7.74 (m, 1H), 2.81 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCN2CCCC[C@@H]2CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 18 h

Procedure:
(R)-2-Hydroxymethyl-1-[3-(4-methoxyphenyl)propyl]piperidine (422 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (210 mg, 2.08 mmol) and methanesulfonyl chloride (238 mg, 2.08 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 18 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-[3-(4-methoxyphenyl) propyl]homopiperidine in the form of a light yellow oil (278 mg, 62%).
Reaction SMILES: Br[C:2]1[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][S:5][CH:6]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:2]4[C:3]([CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:4][S:5][CH:6]=4)=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: OC(CCCc1ccccc1)c1cscc1Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cscc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(4-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.