Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[CH2:37][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 574.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][NH2:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>>[CH3:1][O:2][C:3]([CH2:4][CH2:5][NH:6][C:26]([C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27])=[O:7]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COC(=O)CCN
Product: COC(=O)CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from beta-alanine-methyl ester and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:22][CH:23]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is prepared from 3-methoxybenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 105-107° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.57 (t, J=4.8 Hz, 4H), 2.88 (t, J=5.7 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.85 (s, 3H), 4.31 (t, J=5.4 Hz, 2H), 7.02 (d, J=8.1Hz, 1H), 7.17 (dd, J=2.4 and 8.4 Hz, 1H), 7.42-7.68 (m, 5H), 7.85-7.89 (m, 1H), 8.19-8.22 (m, 1H), 10.24 (s, 1H); MS 407 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:32][CH2:33][C:34](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Cl:32][CH2:33][C:34]1[N:12]([C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 99.9 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-[(methylsulfonyl)amino]pentylcarbamate (7.13 g, 16.3 mmol) was dissolved in 100 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (7.73 g, 48.9 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 200 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g) as an orange foam. The crude material was used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:10]
Reactant: O=[O+][O-]
Reactant: C=CCCCCCCBr
Solvent: ClCCl
Solvent: CO
Product: O=CCCCCCCBr
Temperature: -55 °C
Reaction time: 1 h

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 0.026 mol) in 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -40° C. and treated with O3 while the mixture was cooled to -50 to -60° C. After 30 min the mixture turned bluish and after another 10 min of O3 treatment the mixture was purged with a stream of N2 for 5 min. With the mixture still at -50° C. and covered with a blanket of N2, 2.5 mL of dimethylsulfide was added. This mixture was stirred for 1 h at -40° C., 1 h at -20° C. and then allowed to warm to -10° C. over 1 h. A vacuum from the water aspiration was applied to remove some of the excess dimethylsulfide, and the residue concentrated further on a rotary evaporator (house vacuum). The residue was treated with 10 mL of water and this mixture was extracted with hexane; the organic extracts were washed with water, then brine, dried (MgSO4) and concentrated. A portion of the crude product (0.7 g) was chromatographed under pressure to give 7-bromoheptaldehyde: NMR (CDCl3) δ1.41 (m, 4H), 1.63 (m, 2H), 1.87 (m, 2H), 2.45 (m, 2H), 3.41 (m, 2H), 9.78 (s, 1H).
Reaction SMILES: [Na].CO[C:4]([C:6]1([CH2:17][NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24]C)=[O:22])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5]>CO.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]([CH:20]1[C:4](=[O:5])[C:6]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:7]2)[CH2:17][NH:18][C:19]1=[O:26])=[O:22]
Reactant: CCOC(=O)CC(=O)NCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)NCC2(CN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 90 °C
Yield: 48 %

Procedure:
Sodium metal (870 mg; 38 mmol) is dissolved in methanol (55 ml) and combined with a solution of 3-[(2-ethoxycarbonyl-acetylamino)-methyl]-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester in toluene (165 ml). The reaction mixture is heated to 90° C. for 1 hour, cooled to 7-9° C. and the precipitated white crystals (Na-salt of title compound) filtered off. The crystals are dissolved in water, acidified by the addition of 2N HCl and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and yield the title compound as white crystals (5.6 g; 48%). A second crop of the title compound is obtained by evaporating the above toluene/methanol filtrate to almost dryness, taking up the resin in 2N HCl and extracting with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and yielded the second crop of title compound as brownish solid (3.22 g; 27%).
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(Cl)(Cl)Cl>O>[C:32]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]1[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])=[O:29])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.26 g. of 2,3-dihydroxypropyl-4-(n-hexadecylamino)benzoate and 0.85 ml. of acetic anhydride in 50 ml. of chloroform is heated to reflux for 1 hour and then cooled. The mixture is washed with 90 ml. of water and solid at the interface filtered. The chloroform layer on concentration in vacuo gives a residue which on trituration with methylene chloride yields a white solid (starting material) after filtration. The filtrate on concentration in vacuo yields a pale yellow oil. The oil is stirred overnight with water, extracted with chloroform and azeotroped free of acetic acid with benzene. The pale yellow oil obtained by evaporation in high vacuum is then chromatographed to remove a trace of N,O-diacetylated material. The liquid product is characterized by elemental analyses, infrared spectrum and nuclear magnetic resonance.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH:8][O:9][CH3:10])=[C:5]([S:13][CH3:14])[CH:4]=1.[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22](Cl)=[O:23])[C:18](=[O:25])[O:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[CH:21][C:22]([N:8]([CH2:7][C:6]2[CH:11]=[CH:12][C:3]([F:2])=[CH:4][C:5]=2[S:13][CH3:14])[O:9][CH3:10])=[O:23])[C:18](=[O:25])[O:17]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1SC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(Cc1ccc(F)cc1SC)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution of N-(4-fluoro-2-methylsulfanyl-benzyl)-O-methyl-hydroxylamine hydrochloride (1.19 g, 5 mmol) and (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.953 g, 5 mmol) in CH2Cl2 (20 mL) was added diisopropyethylamine (1.9 mL, 11 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was taken up into ether (150 mL), washed with 1N HCl (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give product as a white solid (1.77 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 7.28–7.23 (1H, m), 6.90 (1H, dd, J=9.5, 2.6 Hz), 6.78 (1H, td, J=8.4, 2.6 Hz), 6.37 (1H, s), 4.88 (2H, s), 3.62 (3H, s), 2.44 (3H, s), 1.71 (6H, s). MS calcd for C16H18FNO5S Na (M+Na): 378.078; found: 378.18.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:21][C:10]3=[CH:11][C:12]4[C:13]([CH3:20])([CH3:19])[C:14](=[O:18])[NH:15][C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][C:13]1([CH3:19])[C:12]2[CH:11]=[C:10]3[NH:21][C:7]([C:3]4[C:2]([NH:1][S:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:30])=[O:29])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[NH:15][C:14]1=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4NS(=O)(=O)c4ccccc4)[nH]c3cc21

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzenesulfonamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.53 mmol) and phenylsulfonylchloride. The title compound was obtained as white powder (66 mg).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:6])[CH:3]([CH3:5])[CH3:4].[CH2:19](Br)[C:20]#[CH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:6][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:20]#[CH:19])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:1])[CH:3]([CH3:5])[CH3:4]
Reactant: COc1cc(C(=O)NC(C)(C)C(C)C)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)NC(C)(C)C(C)C)cc1OC
Yield: 71.7 %

Procedure:
To 10 ml of DMF were added 0.4 g of N-(1,1,2-trimethylpropyl)-4-hydroxy-3-methoxybenzamide, 0.28 g of propargyl bromide and 0.78 g of cesium carbonate and the mixture was heated under reflux for 1 hour. Then, the reaction mixture was concentrated. Dilute hydrochloric acid was added to the residue and extracted with ethyl acetate. After the organic layer was dried over magnesium sulfate, it was concentrated under reduced pressure. The solid obtained was successively washed with hexane and methyl tert-butyl ether to obtain 0.33 g of N-(1,1,2-trimethylpropyl)-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 11 of the present invention) represented by the formula:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH3:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:17](#[N:22])/[CH:18]=[CH:19]/[C:20]#[N:21]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:19]([C:20]#[N:21])[C:18]=2[C:17]#[N:22])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC=CC=Cc1ccc(OCCCC)cc1
Reactant: N#C/C=C/C#N
Product: CCCCOc1ccc(-c2ccc(C)c(C#N)c2C#N)cc1

Procedure:
Using 1-(p-n-butoxyphenyl)-4-methyl-1,3-butadiene and fumaronitrile, 3-(p-n-butoxyphenyl)-6-methylphthalonitrile was obtained by the same method as in Example 1. m.p. was 151.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
2.10 g (purity 74%, 4.72 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoic acid (racemate), 780 mg (4.72 mmol) of ethyl 4-aminobenzoate, 671 mg (4.72 mmol) of Oxima and 735 μl (4.72 mmol) of DIC in 47 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 263 ml of 10% strength lithium chloride solution and 210 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 210 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 2.1 g (75% of theory)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][O:21][C:22]3[C:23]([F:32])=[C:24]([C:28]([F:31])=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[S:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl>[F:32][C:23]1[C:22]([O:21][CH2:20][C:18]2[S:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[N:19]=2)=[CH:30][CH:29]=[C:28]([F:31])[C:24]=1[C:25]([NH2:27])=[O:26]
Reactant: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(OCc4ccccc4)cc3)ns2)c1F
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a solution of 3-[3-(4-benzyloxy-phenyl)-[1,2,4]thiadiazol-5-ylmethoxy]-2,6-difluorobenzamide (0.020 g, 0.04 mmol) in DCM (5 ml) was added methanesulfonic acid (0.15 g, 1.50 mmol) drop wise. The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 5 ml of water and concentrated under vacuum. Added 25 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by ether and DCM washes to get the desired product (0.004 g, 25%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.N([O-])=[O:28].[Na+].[ClH:31]>O>[ClH:31].[OH:28][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g (14.5 mmoles) of 5-amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, the product of Example 64, in 50 ml of 1N aqueous hydrochloric acid, cooled to 0°, was added dropwise a solution of 1.0 g (14.5 mmoles) of sodium nitrite in 5 ml of water. The reaction mixture was stirred overnight at room temperature, filtered and then heated to 90°. A precipitate of 5-hydroxy-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride was collected by filtration, m.p. 218-229°; nmr spectrum of free base: δ 1.0-4.0 (m, 19); 6.3-6.7 (m, 2); 6.7-7.2 (m, 5); 8.7 (s, 1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCBr)cc1
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 4-hydroxybenzonitrile (0.109 g, 0.913 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.930 mL, 9.16 mmol) followed by Cs2CO3 (0.439 g, 1.35 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.156 g, 71.4%). EI-MS Rt (2.10 min).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[NH:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:3]1[C:4]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC(=O)N2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCC2(CCNCC2)N1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate [1031927-12-4] (920 mg, 3.26 mmol) in dichloromethane (10 mL) was added TFA (2.53 mL, 32.6 mmol). The solution was stirred for 40 min at rt. After completion of the reaction the mixture was evaporated under reduced pressure and dried under high vacuum (1.90 g, 100%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.59-8.35 (m, 2H), 7.83 (s, 1H), 3.27-3.14 (m, 2H), 3.12-2.98 (m, 2H), 2.17-2.04 (m, 2H), 1.80-1.57 (m, 8H); LCMS RtA=0.20 min, [M+H]+=169.2].
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].C(O)(C)C>C1COCC1>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCOc1ccccc1
Reactant: O=C1CCCCC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C1CCCCC1(CCCCCOc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 5 phenoxy pentyl bromide (122.0 g, 0.5 mol) and 2-phenylcyclohexanone (104.4 g, 0.6 mol) in 1.5 L THF, NaH (0.55 mol, 24.0 g) was added portionwise, keeping the temperature between 25° to 30° C. After most of the H2 evolution had ceased, the reaction mixture was heated to reflux for 16 hours under a N2 atmosphere. After cooling to room temperature, 50 mL isopropanol was added and the mixture was concentrated in vacuo to half its volume. This residue was diluted with 2 L ether and 1 L H2O. The layers were separated and the aqueous layer was washed one time with 500 mL ether. The combined organic layers were washed two times each with 500 mL H2O, dried (MgSO4), and concentrated in vacuo to give a solid. Recrystallization from petroleum ether yielded 27.5 g (16.4%), mp 69°-72° C., of the desired product.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:20][C:14]1[CH:19]=[CH:18][C:17]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 30 °C
Reaction time: 12 h
Yield: 73.5 %

Procedure:
To the mixture of anhydrous AlCl3 (85 g, 0.64 mole) with dried toluene (90 mL) was added benzoyl chloride (50 mL, 0.43 mole) dropwise at 10±2° C. The mixture was warmed to 30±2° C. and stirred for 12 hours, and then heated to 100±5° C. and stirred for another 2 hr before it was cooled and added into ice water (200 mL) to terminate the reaction. The organic layer was separated and washed successively with water, 5% sodium carbonate and then water again till neutralized. The organic layer was dried over anhydrous magnesium sulfate and evaporated for solvent removal. The residue was recrystallized from n-hexane to obtain 62.1 g 4-methylbenzophenone in a yield 73.5%. mp: 55-57° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[C:21]=[O:22]>ClCCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[NH:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(I)c1
Solvent: ClCCCl
Product: O=C(Nc1cccc(I)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 71 %

Procedure:
To a solution of 3-iodoaniline (438 mg, 2.0 mmol) in 15.0 mL 1,2-dichloroethane at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.304 mL, 2.1 mmol). After 4 hours the precipitant was filtered and rinsed with 10% EtOAc/hexane to give the title compound as a white solid (602 mg, 71%). 1H NMR (DSMO-d6) δ: 9.25 (br. s, 1H), 8.91 (br. s, 1H), 8.57 (dd, J=7.3, 2.1 Hz, 1H), 8.04 (t, J=1.9 Hz, 1H), 7.46-7.54 (m, 1H), 7.42 (dd, J=4.5, 2.2 Hz, 1H), 7.35-7.40 (m, 1H), 7.28-7.33 (m, 1H), 7.06-7.14 (m, 1H)
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCC2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.48 min.; [M+H]+: 409.18 g/mol.