Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:39](Cl)(=[O:55])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[C:39]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:11])[CH3:12])(=[O:55])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 63.4 %

Procedure:
Starting from dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (1 g) and hexadecanoyl chloride (620 mg), dibenzyl N-(N-hexadecanoyl-L-valyl)-L-glutamate (800 mg) was obtained as crystals according to a similar manner to that of Example 24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(#N)C>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 15 h

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (2 grams) was dissolved in 90 ml acetonitrile and then reacted with 2,6-difluorobenzoyl isocyanate (2.6 grams) under nitrogen at room temperature. A solid formed immediately which, after stirring for about 15 hours, was collected and identified as the desired product by NMR analysis, yield 3.4 grams, m.p. 229°-234° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:16]1([CH2:19]Cl)[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH2:19][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:18][CH2:17]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.7 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). Cyclopropyl methyl chloride (2.86 mL, 29.5 mmol) was added to this suspension, and stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.32 g).
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][N:31]=1>C1COCC1.O>[C:18]([O:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:22])[CH:7]=[CH:36][C:33]1[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COP(=O)(CC(=O)CCCCCNC(=O)OC(C)(C)C)OC
Reactant: Cc1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(C=CC(=O)CCCCCNC(=O)OC(C)(C)C)cn1
Yield: 58.9 %

Procedure:
A solution of 24-2 (3.13 g, 9.28 mmol), potassium carbonate (1.75 g, 12.6 mmol), and 2-methyl-pyrimidine-5-carbaldehyde (1.04 g, 8.51 mmol) in THF (20 mL) was warmed to 40 ° C. for 5 h. The mixture was diluted with water and extracted four times with ether. The combined organics were washed with brine and dried (Na2SO4). Purification via silica chromatography (hexane/ethyl acetate) afforded the title compound 24-3 (1.67 g).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[C:2][CH2:3][CH2:4][CH3:5].[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:1]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:4][CH3:5]
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: CCCC#Cc1ccccn1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1c(C(=O)OC)noc1-c1ccccn1
Yield: 5 %

Procedure:
A solution of 2-(pent-1-ynyl)pyridine (150 mg, 1.03 mmol), dimethyl nitromalonate (0.35 mL, 2.58 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.021 mL, 0.103 mmol) in toluene (3 mL) was heated to 170° C. for 120 minutes under microwave. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-propyl-5-(pyridine-2-yl)isoxazole-3-carboxylate (14.3 mg, 0.052 mmol). The compound had an HPLC retention time=3.05 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=247.1. 1H NMR (500 MHz, CDCl3) δ ppm 0.97 (t, 3H), 1.66 (sxt, J=7.48 Hz, 2H), 3.15-3.20 (m, 2H), 4.01 (s, 3H), 7.33 (ddd, J=7.56, 4.81, 1.10 Hz, 1H), 7.83 (td, J=7.77, 1.79 Hz, 1H), 7.91 (d, J=7.97 Hz, 1H), and 8.72 (d, J=4.12 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[Cl:28]N1C(=O)CCC1=O.ClCCl>C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4cccs4)cc3Cl)c2n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4ccc(Cl)s4)cc3Cl)c2n1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (50 mg, 0.126 mmol) in acetic acid (1 ml) was added N-chlorosuccinimide (19 mg, 0.138 mmol) at room temperature. Thirty minutes later, dichloromethane (0.5 ml) was added to the reaction mixture to give a clear transparent solution. Four hours later, N-chlorosuccinimide (19 mg, 0.138 mmol) was further added. The reaction mixture was left standing overnight and concentrated. The residue was purified by p-TLC (chloroform/methanol=40/1) to give the object compound (52 mg, 95.7%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][C:9]3[C:10]([C:32]([OH:34])=O)=[CH:11][N:12]([C:17]4[CH:22]=[CH:21][C:20]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:19][CH:18]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:35]1[N:39]=[CH:38][N:37]([C:40](N2C=NC=C2)=O)[CH:36]=1>>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][NH:39][C:32]([C:10]1[C:9]2[N:8]=[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([C:17]2[CH:22]=[CH:21][C:20]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:19][CH:18]=2)[CH:11]=1)=[O:34]
Reactant: Cc1cccc2cc3c(=O)n(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc(C(=O)O)c3nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Product: Cc1cccc2cc3c(=O)n(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc(C(=O)NCCN(C)C)c3nc12
Temperature: 100 °C
Yield: 74 %

Procedure:
From acid 18p, carried out under nitrogen, with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h. When the amination reaction was complete, the volatiles were removed at reduced pressure with heat (−0.3 mmHg, 100° C., 20 min) and residual N,N-dimethylethylenediamine was removed by azeotropic distillation with toluene (×3). The residue was then boiled in toluene and, while hot, decanted from a brown oil. The toluene was removed at reduced pressure, and the residue was recrystallized from acetonitrile to give the intermediate N-[2-(dimethylamino)ethyl]-6-methyl-1-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxamide as a yellow solid (74%), mp 139-141° C. 1H NMR (CDCl3): δ 1.34 (s, 12H, 4×CH3), 2.31 [s, 6H, N(CH3)2], 2.64 (t, J=6.5 Hz, 2H, CH2CH2NMe2), 2.81 (s, 3H, ArCH3), 3.72 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 7.42-7.48 (m, 3H, H-8,2′,6′), 7.69 (d, J=6.9 Hz, 1H, H-7), 7.80 (d, J=8.1 Hz, 1H, H-9), 7.95 (d, J=8.3 Hz, 2H, H-3′, 5′), 8.68 (s, 1H, H-3), 9.23 (s, 1H, H-10), 10.98 (br t, J=5.4 Hz, 1H, CONH). 13C NMR (CDCl3): δ 18.2 (ArCH3), 24.5 (4×CH3)1 37.2 (CH2CH2NMe2), 45.0 [N(CH3) 2], 58.3 (CH2CH2NMe2), 83.8 (2×C), 109.7 (C-4), 119.4 (C-10a), 125.5 (2×CH, C-2′, 6′), 125.7 (C-9a), 126.4 (CH, C-8), 127.0 (CH, C-9), 132.7 (CH, C-7), 135.6 (2×CH, C-3′, 5′), 140.1 (CH, C-10), 142.0 (C-1′), 142.8 (CH, C-3), 147.8 (C-5a), 148.4 (C-4a), 161.7 (C-1), 164.1 (CONH). C-6 and C-4′ were not observed.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[S:12]1[C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]1=2>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:20]/[NH:19][C:17]([C:16]2[S:12][C:13]3[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=3[CH:15]=2)=[O:18])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)c1cc2ccccc2s1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2cc3ccccc3s2)c2ccccc21
Yield: 82 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and Benzo[b]thiophene-2-carboxylic hydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 82%. 1H NMR (DMSO-d6): δ 0.86 (t, J=6.9 Hz, 3H), 1.26-1.36 (m, 6H), 1.64-1.66 (m, 2H), 3.79 (t, J=7.2 Hz, 2H), 7.19-7.27 (m, 2H), 7.48-7.59 (m, 3H), 7.75 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 8.31 (br s, 1H), 13.65 (br s, 1H). 13C NMR (DMSO-d6): δ 14.33 (CH3), 22.44 (CH2), 26.40 (CH2), 27.41 (CH2), 31.34 (CH2), 39.81 (CH2), 110.71 (CH), 115.52 (C), 119.55 (C), 121.52 (CH), 123.35 (CH), 123.69 (CH), 125.75 (CH), 126.51 (CH), 127.83 (CH), 132.38 (CH), 143.64 (C═N), 161.60 (C═O). HRMS (ES+) calcd for C23H24N3O2S(M+H+), m/e, 406.1596; found, 406.1584.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].N.O.[N-:18]=C=O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=C=O
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.25 grams (0.0442 moles) of 1-t-butylazo-1-isocyanatocyclohexane in 50 ml of methanol in a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, gas addition tube and dry ice condenser was added gaseous ammonia until a gentle ammonia reflux was maintained in the condenser. The reaction was stirred for 90 minutes at room temperature, poured into 300 ml water and the solid that formed was filtered off. The filter cake was air dried leaving 9.0 grams (90% crude yield) of a white powder. The product melted at 115°-117° C. and its infrared spectrum contained a strong carbonyl band at 1670 cm-1 and sharp NH bands at 3250 cm-1 3330 cm-1 and 3440 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:51]([CH2:52][CH3:53])[CH2:49][CH3:50])=[O:23])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCNCC
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.015 g) in DMF (1 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.015 g), HOBT (0.01 g) and triethylamine (0.007 ml) and the mixture was stirred at room temperature for 30 min. Diethylamine (0.007 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>O>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:48]([C:44]4[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=4)(=[O:50])=[O:49])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)c3cccnc3)CC2)n1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 86 %

Procedure:
DIPEA (0.78 mL, 4.48 mmol) was added to a mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (200 mg, 0.449 mmol) and 3-pyridinesulfonyl chloride (159 mg, 0.859 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 18.5 hrs. Water was added and the phases were separated. The organic phase was dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), gave 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(3-pyridinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (227 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:15][Br:36])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(Br)cc(-c2ccc(F)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-4′-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) were combined in tetrahydrofuran (8 mL) and cooled to 0° C. N-Bromosuccinimide (0.59 g, 3.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.60 (m, 1H), 7.50-7.54 (m, 3H), 7.47 (m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1.[Cl-].[NH4+]>O1CCCC1>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([C:23]#[C:24][C:33]2([OH:36])[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[N:11]=[N:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 3.0 g, 9.49 mmol) was dissolved in tetrahydrofuran (24 ml) under nitrogen atmosphere and the resulting solution was cooled to −78° C. n-Butyl lithium (23% solution in hexane; 7.92 ml, 28.48 mmol, 3.0 eq) was added slowly at −78° C., and the resulting mixture was allowed to stir for 30 minutes. Dihydro-2H-pyran-4(3H)-one (1.0 g, 10.44 mmol, 1.1 equiv.) was added slowly to reaction mass and the whole was allowed to warm to room temperature. The crude mixture was then poured into a saturated solution of aqueous ammonium chloride (300 ml) and product was extracted into ethyl acetate (100 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluting with 0-30% ethyl acetate in hexane) to yield the desired material (2.0 g, 501% yield).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:38]([F:43])([F:42])C([O-])=O.[Na+]>COCCOCCOC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:38]([F:43])[F:42])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: CCC[C@H]1CC[C@H](c2ccc(C=C(F)F)cc2)CC1

Procedure:
While 4-(trans-4-n-propylcyclohexyl)benzaldehyde (25 g, 0.11 mol), triphenylphosphine (31 g, 0.12 mol) and diethylene glycol dimethyl ether (25 ml) were heated at 160° C. in nitrogen gas current with stirring, a solution of sodium chlorodifluoroacetate (25 g, 0.16 mol) in diethylene glycol dimethyl ether (70 ml) at 70° C. was dropwise added to the above solution over 2 hours, followed by cooling the resulting solution, filtering it by suction, concentrating the filtrate under reduced pressure, distilling the concentrate under reduced pressure (150° C., 3 mmHg), dissolving the distillate in toluene (100 ml), washing the toluene solution three times with 6N-hydrochloric acid (100 ml) and further with water till the washing water became neutral, drying the toluene solution with anhydrous sodium sulfate, separating the drying agent, distilling off toluene, recrystallizing the residue from a mixed solvent of heptane with ethanol (1:5), dissolving the resulting crystals in heptane, purifying the solution according to silica gel column chromatography, again distilling the resulting solution under reduced pressure, three times recrystallizing the residue from a mixed solvent of heptane with ethanol (1:5) and finally drying the resulting crystals to obtain the objective product (10 g, 0.04 mol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([CH3:36])[CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][C:27]([OH:26])=[CH:28][C:29]=4[CH3:36])=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(O)cc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-hydroxy-2-methylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)[CH3:25]>C(#N)C.O>[CH3:25][C:10]1[NH:11][C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: C[Si](C)(C)Cl
Reactant: COc1ncc(-c2cccc(C#N)c2)c2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1[nH]c(=O)c2ccccc2c1-c1cccc(C#N)c1
Yield: 82.6 %

Procedure:
To a solution of 4-(3-cyanophenyl)-1-methoxyisoquinoline (200 mg, 0.73 mmol) in acetonitrile (6 mL) is added sodium iodide (219 mg, 1.46 mmol) followed by chlorotrimethylsilane (186 μL, 1.46 mmol) and the mixture is heated at reflux for 1.5 hr. The cooled reaction is diluted with water (15 mL) and the solids are collected by filtration, washed with water and dried to give 3-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)benzonitrile (157 mg, 83% yield). 1H NMR (δ ppm) 11.55 (1H, s), 8.22 (1H, d), 7.95 (1H, d), 7.82 (1H, s), 7.72 (1H, t), 7.66 (1H, m), 7.60 (1H, m), 7.47 (1H, t), 6.94 (1H, d), 1.99 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.[Br:18]Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:18][C:17]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3n(c2Br)CCCC3)c(Cl)c1
Reaction time: 2 h

Procedure:
To 0.8 g (3.0 mmol) of the above 2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine stirring in 50 ml of methylene chloride at room temperature, 0.5 g (3.1 mmol) of bromine in 5 ml of methylene chloride was added dropwise. The solution was stirred for 2 h. Another 20 ml of methylene chloride and excess saturated aqueous sodium bicarbonate were added. After sufficient mixing, the methylene chloride layer was separated, washed with water and brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo gave a yellow solid residue which was purified by silica gel column chromatography (5:1 followed by 3:1 followed in turn by 1:1 hexane/ethyl acetate) to yield a 0.55 g sample of the title compound (m.p. 112°-113° C.).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[C:25]([O:29][C:30](=[O:37])[NH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:37])[NH:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:8](=[O:24])[NH:9][CH:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:15]2)[CH2:33]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)CC1
Temperature: 100 °C

Procedure:
(4-tert-Butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.