Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li][CH2:34]CCC.[CH:38](=O)/[CH:39]=[CH:40]/[CH2:41][CH2:42]/[CH:43]=[CH:44]\[CH2:45]C>>[CH3:34][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)=[CH:13]/[CH:45]=[CH:44]/[CH2:43][CH2:42]/[CH:41]=[CH:40]\[CH2:39][CH3:38]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: CC/C=C\CC/C=C/C=O
Agent: [Br-]
Product: CC/C=C\CC/C=C/C=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.40 g, 4.83 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.0 mL, 4.83 mmol, 1.0 equiv.) and (2E,6Z)-Nona-2,6-dienal (1.00 g, 7.24 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 0.90 g (67%) of the title compound as a a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.[Pd]>[NH2:17][C:12]1[CH:11]=[C:10]([CH:3]([C:2]([F:21])([F:1])[F:20])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CCOC(=O)C=C(c1ccc(F)c([N+](=O)[O-])c1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)c(N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (16.3 mmol) of ethyl 4,4,4-trifluoro-3-(4-fluoro-3-nitrophenyl)but-2-enoate were dissolved in 133 ml of ethanol, and 866 mg of palladium on carbon (10%) were added under argon. At RT, the reaction mixture was stirred vigorously under an atmosphere of hydrogen (atmospheric pressure) overnight. The mixture was then filtered off through celite and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 3.91 g of the target product (85.9% of theory).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.I[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[F:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:15][CH2:16][CH3:17])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: CCCI
Reactant: O=c1[nH]c2ccc(F)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)oc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To 670 mg (16.74 mmol) of hexanes washed sodium hydride in 20 ml DMF was added a solution of 2.33 g (15.22 mmol) 6-fluoro-1,3-benzoxazolin-2(3H)-one in 40 ml DMF. The reaction was stirred for 10 minutes before 3.11 g (18.3 mmol) 1-iodopropane was added and then stirred for 3 hr at room temperature. After pouring into 50 ml of ice/water, the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic layers were washed with water (1×100 ml), dried over Na2SO4 and evaporated to dryness in vacuo to give 2.2 g (75% yield) of the alkylated product as a brown solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[O:29][C:28]([C:31]([NH:33][C@@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:32])=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C1COCC1>CN(C=O)C>[ClH:12].[N:36]12[CH2:37][CH2:38][CH:39]([CH2:40][CH2:41]1)[C@@H:34]([NH:33][C:31]([C:28]1[O:29][C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][NH:14][C:10]([NH:9][CH3:8])=[O:11])=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=1)=[O:32])[CH2:35]2
Reactant: CN=C=O
Reactant: NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Reaction time: 18 h

Procedure:
62.2 μl (0.45 mmol) of triethylamine and 53 μl (0.89 mmol) of methyl isocyanate are added to a solution of 100 mg (0.22 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride (Example 152) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 75 mg (66% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](O)[CH:9]=2)=[CH:6][C:5]([OH:15])=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:25](=[O:28])([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:28][CH2:25][CH2:8][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=1
Reactant: Oc1cccc(-c2cc(O)ccc2Br)c1
Reactant: CCCCCCCCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cccc(-c2cc(OCCCCCCCC)ccc2Br)c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
6-bromo-biphenyl-3,3′-diol (5.92 g, 22.43 mmol) prepared in Example 2, 1-octylbromide, potassium carbonate (18.60 g, 134.56 mmol) and potassium iodide (3.72 g, 22.43 mmol) were dissolved in dimethylformamide (60 ml), followed by heating for about 24 hours at about 150° C. After cooling to room temperature, distilled water was added to the resultant and stirred for about 10 minutes, followed by filtering three times with hexane, washing three times with distilled water, drying with sodium sulfate. Then, the hexane was concentrated under reduced pressure. Purification by silica gel chromatography using 4% dichloromethane in hexane gave 2-bromo-5,3′-bis-octyloxy-biphenyl corresponding to the compound III of the reaction scheme 1 (Yield: 6.36 g, 58.1%), R1 and R2 in the formula of the compound III being each independently octyl. The product was identified through the NMR spectrum and element analysis that it had the identical structure with the compound III.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][N:9]([C@H:10]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:11][CH2:12][CH3:13])[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([CH3:34])[CH:33]=[C:25]([CH3:24])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC[C@H](N(NC(=O)OC(C)(C)C)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
(S)—N′-(1-tert-Butyl-butyl)-hydrazinecarboxylic acid tert-butyl ester (1 g, 4.09 mmoles) was dissolved in ca. 3 mL methylene chloride in a vial with a magnetic stir bar. A solution of 0.8 g K2CO3 (5.79 mmoles) in ca. 2 mL water was added, followed by 0.81 g (4.80 mmoles) 3,5-dimethylbenzoyl chloride. The reaction was stirred overnight, first on ice, and then allowed to warm to room temperature. Several mL each water and methylene chloride were then added to dissolve all solids. The aqueous layer was removed and the organic layer was dried over solid MgSO4. TLC indicated that the reaction was ca. 95% complete. The mixture was filtered through some glass wool into a vial. Solvent was evaporated with a stream of N2, chasing with 3:1 hexanes:ether and pentane. The residue was manipulated with a spatula to initiate crystallization, and after complete solidification, was triturated thrice with 2-3 mL pentane in a small fitted glass funnel. After drying in air, 300 mg (19.5%) (S)—N′-(1-tert-Butyl-butyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester was obtained, indicated by TLC to be quite pure, chiral HPLC indicated e.e=93.3%. The product was dried in a vacuum oven at 50° C. for melting point determination. Rf=0.42 (4:1 hexanes:ethyl acetate, UV (strong), I2 (weak) visualization); mp=115.5-117.5° C.; [α]25589−30.18 (c 2.02, CH3OH), 1H NMR (400 MHz, CDCl3) δ 7.15-7.03 (m, 3H), 6.07+6.00 (s+d, 1H), 4.52+4.40 (2dd, 1H), 2.32+2.28+2.23 (3s, 6H), 1.85-0.89 (m, 25H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:13]C=O)([CH3:12])[CH3:11].Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:13])([CH3:11])[CH3:12]
Reactant: CC(C)(Cc1ccc(F)cc1F)NC=O
Agent: Cl
Product: CC(C)(N)Cc1ccc(F)cc1F

Procedure:
Reaction of 22.0 g (100 mmol) of N-[2-(2,4-difluorophenyl]-1,1-dimethylethyl]formamide analogously to the method for Example 10(c). Yield: 16.0 g (72%, hydrochloride); melting point: 201° C.-203° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][CH:10]([CH2:12]O)O>>[N:4]1[C:3]2[C:2](=[N:1][CH:9]=[CH:10][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccnc1
Reactant: OCC(O)CO
Product: c1cnc2cccnc2c1

Procedure:
Thus 3-amino pyridine III may be condensed with a glycerol of formula IV to give the ##STR3## 1,5-naphthyridine of formula V which is reduced e.g. by hydrogenation over platinum oxide to the 1,2,3,4-tetrahydro-1,5,-naphthyridine of formula (VI). In formula IV, V and VI R1, R2 and R3 are as defined in connection with formula I.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:25]>C(Cl)Cl>[ClH:25].[ClH:25].[CH3:17][C@H:16]1[C:9]2[C:8]([N:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Yield: 99 %

Procedure:
(S)-tert-butyl 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 4 mL) in DCM (20 mL) for 6 hours to provide the (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.18 g, 99%). MS (APCI+) [M+H] +233.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[C:12](N(OC)C)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[CH:12]=[O:13])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide (1.13 g, 3.02 mmol) in THF (36.8 mL) at −50° C. was added 1.0 M diisobutylaluminum hydride in hexane (15.1 mL, 15.1 mmol) and the resulting solution was stirred at −50° C. to −30° C. for 2 hours. The reaction was quenched with saturated ammonium chloride (10 mL) and allowed to warm to room temperature. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→70/30) to give 699 mg of the title compound as a white solid (73% yield). LC/MS (FA) ES+ 315. 1H NMR (300 MHz, CDCl3) δ: 10.16 (s, 1H), 8.78-8.76 (m, 2H), 7.85-7.83 (m, 2H), 7.30-7.25 (m, 4H), 4.47 (s, 2H).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](O)=[O:18].N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:14]([Cl:13])[CH:15]=3)[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 3,4-dichlorobenzoic acid (Aldrich) according to methods A and C; yield 39 mg, 0.10 mmol (49%): 1H NMR (300 MHz, methanol-d4) δ 2.06-2.27 (m, 6H), 2.46 (s, 2H), 3.48 (d, J=12 Hz, 2H), 3.55 (s, 2H), 3.81 (d, J=13 Hz, 2H), 4.25 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.80 (dd, 1H), 8.07 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. C16H18Cl2N2O.HCl.0.4HCl.0.15C4H8O2: C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH3:17]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:17])=[S:10])[CH:7]=1
Reactant: N
Reactant: Cc1ccc(N2CCOCC2)c(N=C=S)c1
Product: Cc1ccc(N2CCOCC2)c(NC(N)=S)c1

Procedure:
Reaction of 5-methyl-2-morpholinophenyl isothiocyanate (15 g) with 33% ethanolic ammonia solution for 48 hours at room temperature gave 1-(5-methyl-2-morpholinophenyl)thiourea as a pale yellow solid (m.p. 181°-182° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16](B(O)O)[CH:17]=1)[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[C:12]([O:11][CH2:9][CH3:10])[CH:17]=[CH:16][C:15]=2[F:21])=[N:3][CH:4]=1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Brc1ccc(Br)nc1
Product: CCOc1ccc(F)c(-c2ccc(Br)cn2)c1
Yield: 47 %

Procedure:
Obtained (1.18 g, yield 47%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (8.44 mmol, 2.0 g), 5-ethoxy-2-fluorophenylboronic acid (8.43 mmol, 1.55 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>C(#N)C>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1[nH]cnc1C
Yield: 58.8 %

Procedure:
A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (5.1 g.) and methyl isocyanate (2.0 g.) in acetonitrile was heated for 18 hours in a pressure vessel at 100°. After cooling, the solid obtained was collected and recrystallised from isopropyl alcohol-acetonitrile to give N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]urea (4.0 g.) m.p. 158°-159°. (Found: C, 47.4; H, 7.1; N, 24.5; S, 14.1. C9H16N4OS requires: C, 47.3; H, 7.1; N, 24.5; S, 14.0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH:10]([C:18](=[O:20])[NH2:19])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[C:18]([NH2:19])=[O:20])[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H]1CNCC[C@H]1N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.66 g. 2.21 mmol) in anhydrous DMF (13 mL) was added formamide (370 μL, 9.32 mmol). The mixture was heated to 100° C. and a solution of sodium methoxide in MeOH (25 w/w. 330 μL, 1.44 mmol) was added with heating being continued for 2 h. The reaction mixture was cooled to RT, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (40 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (280 mg, 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:18]#[CH:19]>>[OH:13][C:7]1([CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([C:19]#[C:18][CH2:17][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])[CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OC1(CCc2cccc(Br)c2)CCCCC1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CC#Cc1cccc(CCC2(O)CCCCC2)c1

Procedure:
Coupling of 1-(3-bromophenethyl)cyclohexanol with 2-(prop-2-ynyl)isoindoline-1,3-dione following the method described in Example 12 gives 2-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)prop-2-ynyl)isoindoline-1,3-dione.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20](O)=[O:21]>>[CH3:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: CC(C)(C)CC(=O)O
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: CC(C)(C)CC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 3,3-dimethylbutanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.43-8.46 (m, 1H), 8.13-8.16 (m, 1H), 8.03-8.09 (m, 2H), 2.23 (s, 2H), 1.07 (s, 9H); MS (ESI−) M/Z 326 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1[NH:19][CH:20]1[CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[C:10](=[O:23])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:19]([CH:20]2[CH2:21][CH2:22]2)[C:24]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Yield: 46.4 %

Procedure:
A solution of N-benzyloxy-4-chloro-2-cyclopropylamino-5-fluoro-benzamide (Example D-3, 3.00 g, 8.96 mmol) in 1,4-dioxane (50 mL) was reacted with a 20% solution of phosgene (7.00 mL, 9.86 mmol) in toluene in a sealed tube. The mixture was heated to reflux for 24 hours, then cooled and quenched with H2O. The mixture was extracted three times with ethyl acetate, the organic layers combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 1.5 g of the title compound as a solid.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](OCC)=[O:15])=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([NH2:29])[CH3:28]>CO>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](=[O:15])[NH:29][CH2:27][CH3:28])=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Yield: 82.2 %

Procedure:
In methanol, 2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and a 70% aqueous solution of ethylamine were processed as in Example 43, whereby the title compound was obtained in a yield of 82.2%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:20][C@H:19]1[CH3:30])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.P([O-])(O)(O)=O.[K+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH:28]=[O:29])[CH2:20][C@H:19]1[CH3:30])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@@H]1CN(CCCO)C(=O)CCN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H]1CN(CCC=O)C(=O)CCN1C(=O)OC(C)(C)C
Temperature: -6 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
To a solution of 0.161 ml (1.84 mmol, 1.15 eq.) of oxalyl chloride in 9 ml dichloro-methane at −50 to −60° C. was added a solution of 0.272 ml (3.83 mmol, 2.4 eq.) dimethyl-sulfoxide in 1.5 ml dichloromethane within 5 min. The solution was stirred for 5 min and a solution of 0.457 g (1.60 mmol) of (R)-4-(3-hydroxy-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example 1B) in 4.5 ml dichloromethane was added within 5 min. The mixture was stirred for 15 min and 1.11 ml (7.98 mmol, 5 eq.) of triethylamine was added within 5 min. The suspension was stirred for 3.5 h and slowly warmed to −6° C. The reaction was neutralized with cold 10% aq. potassium dihydrogenphosphate solution (adjusted with solid potassium dihydrogenphosphate to pH 4-5) and extracted with ethyl acetate (3 times). The organic phases were washed with fresh sat. aq. sodium hydrogencarbonate solution and 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to give 0.418 g (92%) of the title compound as colorless oil. MS: 285.1 (MH+).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[C:35]([O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:24][CH:25]=3)[C:20]([CH3:30])=[C:19]2[CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1Cl
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:4]([O:14]COC)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.Cl>O1CCOCC1>[CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:4]([OH:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COCOc1c(-c2ccc(OC)cc2)c(C)cc2cc(OC)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2O)cc1
Yield: 84.2 %

Procedure:
As described for Example 2 (Step 5), treatment of 3-Methyl-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}-2-[4-(methyloxy)phenyl]naphthalene (44) (0.41 g, 1.21 mmol) with 4 M HCl in dioxane at room temperature yielded 0.30 g (89%) of the title compound (45) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.16 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 5.23 (s, 1H), 7.02-7.10 (m, 4H), 7.20 (s, 1H), 7.26 (d, J=8.6 Hz, 2H), 8.07 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 295 (M+H)+, m/z 291 (M−H)−.