Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:9]=3[NH:10]2)=[CH:6][CH:5]=1.[CH3:26]I.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][C:15]([CH3:17])([CH3:18])[N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:9]=3[N:10]2[CH3:26])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3cc(Br)ccc3c2CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3ccc(Br)cc31)CC(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
NaH (60% dispersion in oil, 42 mg, 1.1 mmol) was added to a solution of tert-butyl 7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (200 mg, 0.528 mmol) in DMF (10 mL) under N2, and the resulting suspension was stirred at 25° C. for 30 min. MeI (0.05 mL, 0.8 mmol) was added to the suspension, and the resulting suspension was stirred at 25° C. for 1 h. H2O was added, and the resulting solid was collected by filtration. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (145 mg, 70%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=1.5 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 1H), 4.62 (s, 2H), 3.61 (s, 3H), 2.77 (s, 2H), 1.52 (s, 6H), 1.49 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:5][CH:4]=1)=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[N:24]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(C=O)cc2)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(CN3CCCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 8 (2.0 g), piperidine (0.91 mL), and acetic acid (0.42 mL) in DCM (100 mL) was treated with sodium triacetoxyborohydride (1.95 g) at room temperature. After 16 h, the resulting mixture was treated with 10% aqueous sodium hydroxide (30 mL). The aqueous phase was extracted with DCM (2×300 mL). The combined organic phases were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was diluted in DCM (100 mL) and passed through a pad of silica gel. The pad was washed with DCM (3×200 mL). The combined filtrate was concentrated under reduced pressure, giving the title compound as a brown oil (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1Cl

Procedure:
Prepared from 20 mg (0.075 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 58 mg (0.25 mmol) of 3-chloro-4-methyl-benzenesulfonyl chloride in 0.15 mL pyridine using procedure x. After the sulfonylation was complete, 3 mL methanol, 0.5 mL water and 35 mg sodium hydroxide were used. Yield: 9 mg of a yellow solid. LC-MSD, m/z for C20H14Cl2N4O3S [M+H]+=460.9, 462.9
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:6]([CH3:16])[N:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[CH:8]=[C:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[N:6]([CH3:16])[N:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCOC(=O)COc1cc(C(=O)O)nn1C
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)n(C)n3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[3-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:10]=[CH:11][C:12]2[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]([CH3:25])[C:13]=2[N:14]=1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]([CH3:25])[C:13]=3[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn(C)c2nc(Cl)ncc2c1=O
Reactant: CN1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 2 h
Yield: 56.5 %

Procedure:
1.5 g of N-methylpiperazine are added to a stirred suspension of 2 g of 2-chloro-5-oxo-6-carbethoxy-8-methyl-5, 8-dihydro-pyrido(2,3-d)pyrimidine in 20 cm3 of absolute ethanol. The reaction takes place with evolution of heat. After standing for 2 hours at room temperature, the solvent is evaporated in vacuo, the residue is taken up in water and the precipitate is filtered off, washed, dried in vacuo and recrystallised from benzene: 1.4 g (58%) of 2-(4'-methyl-piperazino)-5-oxo-6-carbethoxy-8-methyl-5,8 -dihydro-pyrido(2,3-d)pyrimidine are obtained.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:15]S([O-])(=O)=O.C[S+](C)C.ClCCl>O>[O:3]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:15]1
Reactant: CS(=O)(=O)[O-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC2(CC1)CO2
Yield: 72 %

Procedure:
A solution of 47% sodium hydroxide (15 ml), ethyl 4-oxopiperidine-1-carboxylate (4.53 ml, 30 mmol), trimethylsulphonium methanesulphonate (7.36 g, 39 mmol) (Syn. Comm., 1985, 15, 749) and dichloromethane (30 ml) was heated to 50° C. for 16 h, cooled, diluted with water (30 ml), and extracted with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica, eluting with 2% methanol/dichloromethane to give the product as a mobile yellow oil (4.0 g), MS (+EI)m /z 185; 1H NMR (360 MHz) (CDCl3) 4.15 (2H, q, J7.1 Hz), 3.78 (2H, brs), 3.46 (1H, ddd, J3.7, 9.6, 13.3 Hz), 2.71 (2H, s), 1.87-1.79 (2H, m), 1.49-1.43 (2H, m), 1.28 (3H, t, J7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16]
Reactant: Cc1cccc(C=O)c1O
Reactant: CC(C)(C)NO
Product: Cc1cccc(C=[N+]([O-])C(C)(C)C)c1O

Procedure:
The title compound was prepared according to the procedure described in Example 9 using 2-hydroxy-3-methylbenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 94% yield as a yellow crystalline solid, m.p. 59.2° C. (Rf=0.71 on a silica gel plate using 1:1 hexanes/EtOAc as an eluant).
Reaction SMILES: C([O:5]C([NH:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:42].O1CCOCC1>>[OH2:5].[ClH:42].[NH2:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCc1ccccc1
Product: O

Procedure:
A solution of [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide (610 mg.) in hydrogen chloride-dioxane (3.9 N, 10 ml.) was stirred at room temperature for 40 minutes, then concentrated under vacuum. Ether was added to the residue, the solution was concentrated under vacuum, and the process was repeated. A solution of the residue (502 mg.) in water (20 ml.) was filtered and lyophilized, affording as an amorphous off-white solid L-tyrosyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride monohydrate (473 mg.), whose free base is the compound of Formula II wherein Q is Met, R1, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: [BrH:1].Br[CH:3]([CH3:6])[CH2:4][NH2:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>N1C=CC=CC=1.CCOCC>[Br:1][CH2:6][CH2:3][CH2:4][NH:5][S:8]([CH3:7])(=[O:10])=[O:9]
Reactant: Br
Reactant: CC(Br)CN
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)NCCCBr
Reaction time: 0.25 h

Procedure:
To a cooled solution of 2-bromopropylamine hydrobromide (43.8 g., 0.20 mole) in pyridine (100 ml.) was added over a period of 40 minutes methanesulfonyl chloride (15.2 ml., 0.20 mole). The reaction mixture was stirred for 15 minutes and then diluted with ether. The remaining solid was filtered off, washed with about 200 ml. of acetone. The filtrate and washes were concentrated in vacuo. The residue was extracted with three 100 ml. portions of acetone. Upon evaporation of the acetone, 30.4 g. of a thick oil representing the title compound. The product was confirmed by infrared analysis and nuclear magnetic resonance.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.ClCCl.CO.N>>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:1](=[O:5])[C:2]#[CH:3])=[CH:9][CH:8]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: C#CC(=O)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4-chloroaniline. Yield: 0.56 g (31.2% of theory); C9H6ClNO (M=179.60); calc.: molecular ion peak (M−H)−: 178/180; found: molecular ion peak (M−H)−: 178/180; Rf value: 0.53 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.20 min, MH+459. NMR: δH [2H6]-DMSO 12.71, (1H, b), 9.31, (1H, t), 9.17, (1H, d), 8.39, (1H, dd), 8.22, (1H, s), 8.07, (1H, d), 7.83, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.29-7.25, (2H, m), 6.94, (2H, m), 6.84, (1H, d), 4.52, (2H, d), 3.75, (3H, s), 2.45, (3H, s).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.[CH3:15]O>>[ClH:3].[NH2:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CO
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (301 mL, 0.6 eq) was added dropwise to a suspension of cis-4-amino-1-cyclohexane carboxylic acid (6) (984 g, 6.87 mol) in methanol (4.82 L) and stirred for 6 hours at room temperature, and the mixture was allowed to be stand for 3 days. The reaction mixture was concentrated under reduced pressure and isopropyl ether was added to the mixture. The appeared crystals were collected by filtration to obtain methyl cis-4-amino-1-cyclohexane carboxylate hydrochloride (1086 g, 81.6%). The mother liquor was concentrated under reduced pressure and methanol (50 mL) and isopropyl ether (1.0 mL) were added to the residue. The appeared crystals were collected by filtration to obtain second crystals of (7) (94 g, 7.0%).
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][O:12][CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](Cl)=[O:30])[C:26]([C:32](F)([F:34])[F:33])=[N:25]1>ClCCl>[I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([O:12][CH3:13])[C:29]([C:27]3[C:26]([CH:32]([F:34])[F:33])=[N:25][N:24]([CH3:23])[CH:28]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: CONC1CCCCc2ccc(I)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1CCCCc2ccc(I)cc21
Temperature: 24 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of N-(3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (77 mg; 0.24 mmol), prepared as described in example P3c and triethylamine (0.037 ml; 0.26 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (47 mg; 0.24 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. The mixture diluted with dichloromethane (10 ml), washed with 1M sodium hydroxide (1 ml), 1M hydrochloric acid (1 ml) and brine (1 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude (190 mg) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.101 g (88% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as a yellow solid oil.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:34][C:4]3[CH:3]=[CH:10][CH:9]=[CH:8][C:5]=3[CH3:6])[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: Cc1ccccc1CN1C[C@H]2CC[C@H](NC(=O)C(c3ccccc3)C(C)C)[C@H]2C1

Procedure:
The title compound was prepared by substituting 2-methylbenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57-8.51 (m, 1H), 7.63 (dd, J=3.5, 7.1, 2H), 7.43-7.36 (m, 1H), 7.36-7.30 (m, 3H), 7.25 (dd, J=6.9, 9.6, 2H), 7.20-7.13 (m, J=10.0, 2H), 4.31 (dd, J=5.5, 11.3, 1H), 3.57 (d, J=13.1, 0.5H), 3.48 (d, J=13.0, 0.5H), 3.39 (d, J=13.0, 0.5H), 3.29 (d, J=13.0, 0.5H), 3.21 (d, J=10.3, 1H), 2.92 (dd, J=2.8, 9.0, 0.5H), 2.68-2.60 (m, 1H), 2.60-2.53 (m, 1H), 2.51-2.45 (m, 1H), 2.35 (s, 1.5H), 2.30 (s, 1.5H), 2.28-2.17 (m, 2H), 2.15-2.06 (m, 1H), 1.84 (ddd, J=6.8, 12.4, 20.0, 1H), 1.76-1.62 (m, 1H), 1.42 (dt, J=7.2, 19.2, 0.5H), 1.33 (dt, J=7.0, 12.5, 0.5H), 1.29-1.22 (m, 0.5H), 1.20 (d, J=6.5, 3H), 0.70 (d, J=6.7, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH2:15][N:1]2[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]2)[CH2:18][CH2:17]1.[CH:16]1([CH2:15][N:3]2[CH:4]=[C:5]([CH:6]=[O:7])[N:1]=[CH:2]2)[CH2:18][CH2:17]1
Reactant: O=Cc1cnc[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cn(CC2CC2)cn1
Product: O=Cc1cncn1CC1CC1
Yield: 34 %
Yield: 33 %

Procedure:
According to Step 1 of Reference Example 8-47, by use of 1H-imidazole-5-carbaldehyde (400 mg, 4.16 mmol) dissolved in N,N-dimethylformamide (6 mL), potassium carbonate (1.15 g, 8.32 mmol) and (bromomethyl)cyclopropane (0.444 mL, 4.58 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=30/1, 50/1) was performed to give 1-(cyclopropylmethyl)-1H-imidazole-5-carbaldehyde (212 mg, yield: 34%) and 1-(cyclopropylmethyl)-1H-imidazole-4-carbaldehyde (209 mg, yield: 33%). 1-(cyclopropylmethyl)-1H-imidazole-5-carbaldehyde
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[OH-].[Li+]>O1CCCC1.C(O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])=[C:7]2[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(Br)cccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 20.9 %

Procedure:
To a solution of ethyl 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 0.061 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 3 mL) was added lithium hydroxide (7 mg, 0.31 mmol) and the reaction was heated to 50° C. overnight. Crude reaction purified by reverse phase HPLC (Gemini, 40-100% ACN/H2O+0.1% TFA). Product lyophilized to give a white powder (5.9 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.77 (d, J=6.0 Hz, 1H), 7.58 (s, 2H), 7.55 (as, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (m, 1H), 5.17 (s, 1H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C23H21BrClO3: 460.8. found; 460.2.
Reaction SMILES: ClC[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]2([CH3:18])[CH3:17])=O.[Cl-].[C:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[NH2+])=[CH:27][CH:26]=1)([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41](C)C=O>>[C:20]([C:25]1[CH:26]=[CH:27][C:28]([C:29]2[N:31]=[C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=4[CH:6]=3)[NH:41][CH:40]=2)=[CH:32][CH:33]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1ccc(C(N)=[NH2+])cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2c[nH]c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)cc1
Reaction time: 0.17 h

Procedure:
2.6 g (10 millimoles) of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (for preparation see Example 28), 2.1 g (10 millimoles) of 4-carbethoxybenzamidinium chloride and 5 g of potassium carbonate in 100 ml of dimethylformamide were refluxed for 1 hour. After cooling, the mixture was poured onto water and stirred for 10 minutes, and the precipitate formed was filtered off under suction. Purification by column chromatography (silica gel; 9:1 n-heptane/ethyl acetate) gave 0.3 g of the title compound of melting point 186°-188° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)[CH3:18]
Reactant: CN1CCN(CCCN)CC1
Reactant: CCOC(=O)C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
A solution of 4-(3-aminopropyl)-1-methylpiperazine (3.1 mL, 20 mmol) in MeOH (50 mL) was cooled in an ice bath and treated with ethyl glyoxylate (50% solution in toluene, 5.6 mL, 27 mmol) and AcOH (3 mL). After stirring for 15 min, NaBH3CN (1.37 g, 21.8 mmol) was added and the mixture was allowed to stir for 7 h while slowly warming to room temperature. The mixture was diluted with saturated aqueous NaHCO3 (150 mL) and then extracted with EtOAc (3×100 mL) followed by CH2Cl2 (3×100 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (1.81 g, 38%) as a colorless oil: MS (ESI) m/e 244 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[Cl:13]C[C:15]([NH:17]CO)=O.O>C(O)(=O)C.S(=O)(=O)(O)O.C(O)C>[ClH:13].[NH2:17][CH2:15][C:10]1[CH:11]=[C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCC(C)(C)c1ccc(O)c(CN)c1
Product: Cl
Reaction time: 12 h
Yield: 37 %

Procedure:
A mixture of 4-(1,1-dimethylpropyl)phenol (32.8 g., 0.2 mole) and 2-chloro-N-(hydroxymethyl)acetamide (24.6 g., 0.2 mole) in acetic acid (200 ml.) and 96% sulfuric acid (20 ml.) is stirred at 20° for 12 hours and then poured into cold water (1 l.). The solid that separates is extracted with ether and the ether extract is washed with water and salt brine and evaporated to dryness. The oily residue is dissolved in a mixture of 12N hydrochloric acid (100 ml.) and ethanol (100 ml.). The mixture is refluxed for 7 hours. The mixture then is evaporated to dryness under reduced pressure. The residue is triturated with dry ether to obtain a sticky white solid that is dissolved in hot ethanol (50 ml.) and precipitated in the cold by addition of ether (800 ml.). The solid is then crystallized from ethanol - 12N hydrochloric acid (1:10) to obtain 2-aminomethyl-4-(1,1-dimethylpropyl)phenol hydrochloride (17 g.), m.p. 191°-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:31]([NH2:33])[CH3:32])[N:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[N:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)nnc1OCC(F)(F)C(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)C(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (612 mg, orange oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (605 mg, 2.17 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (600 mg, 1.98 mmol, Amine-77, single enantiomer) in a similar manner to Intermediate-2.