Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:32])=[C:13]([C:27](OCC)=[O:28])[C:14](=[O:26])[N:15]2[CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:32])=[C:13]([C:27]([NH:37][CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:28])[C:14](=[O:26])[N:15]2[CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CCN2CCOCC2)c1=O
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(CCN2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-(2-morpholin-4-ylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.01 (1H, br d, J=5 Hz), 8.70 (1H, s), 8.61 (1H, s), 7.39 (2H, d, J=7.7 Hz), 7.30 (2H, t, J=7.7 Hz), 7.21 (1H, m), 4.89 (2H, m), 4.52 (1H, m), 4.26 (4H, m), 4.07 (2H, m), 3.50 (2H, m), 3.18 (2H, m), 3.09 (2H, m), 2.43 (2H, m), 2.06 (2H, m), 1.81 (2H, m); HRMS calcd for C26H30N4O4+H+: 463.2345. Found: 463.2343.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:14]1[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:15]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Yield: 92.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl bromide were reacted to yield the title compound as a yellow crystalline powder (yield: 92.1%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and cyclopropanecarboaldehyde (0.3 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: C1CCNCC1
Product: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and piperidine (0.039 ml, 0.39 mmol). Pale yellow solid (52 mg, 60%). LC-MS (ESI): 443 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([C:30](=[O:32])[CH3:31])=[CH:25][C:24]=3[F:33])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].C(OCC)(=O)C>CO.C([O-])(O)=O.[Na+]>[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([CH:30]([OH:32])[CH3:31])=[CH:25][C:24]=3[F:33])[CH2:21][CH2:22]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(=O)c1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(C)O)cc3F)CC2)CC1
Reaction time: 1 h

Procedure:
NaBH4 (0.15 g, 3.9 mmol) was added at 0° C. to a stirred solution of 50a (0.15 g, 0.34 mmol) in 5 mL of methanol. After 1 h, the mixture was diluted with 10 mL of saturated NaHCO3 and stirred for 20 minutes. The mixture was poured into ethyl acetate (25 mL), washed twice with brine (25 mL), dried and concentrated under vacuum. The residue was purified on an AS-H column (elution with 5% EtOH+0.1% triethylamine in hexane) to afford the 2 enantiomers of 4-{1-[2,5-difluoro-4-(1-hydroxy-ethyl)-phenyl]-piperidin-4-ylideneaminooxy}-piperidine-1-carboxylic acid isopropyl ester 50-1, LC-MS 422.2 (MFE-18), tR=6.45 (Method 2). EC50: 48 nM. 78 mg of the first enantiomer and 46 mg of the second enantiomer were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10]COCC[Si](C)(C)C)=[CH:4][N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[N:28]=[C:29]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]3[CH3:48])[NH:30][C:31]=2[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:23]=[CH:24][C:25]=1[F:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=[N:3][C:2]=1[N:45]1[CH2:46][CH2:47][N:42]([C:29]2[NH:30][C:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][CH:33]=3)=[C:27]([C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=3)[N:28]=2)[C@H:43]([CH3:48])[CH2:44]1
Reactant: C[Si](C)(C)CCOCOCc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1

Procedure:
A mixture of 2,3-dichloro-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)pyridine from step (a) above (80 mg, 0.26 mmol), (2R)-1-(4-(3,4-difluorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-2-methylpiperazine (100. mg, 0.236 mmol, Example 1(d)), and DIEA (0.082 mL, 0.47 mmol, Aldrich) in NMP (0.7 mL) was subjected to microwave irradiation at 170° C. for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:9) as the eluant to give the title compound as a light brown solid. MS (ESI, positive ion) m/z: 694 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1(B(O)O)[CH:23]=[C:22]([CH3:24])[O:21][NH:20]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:19]1[C:23]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([CH3:15])[C:5]3=[C:4]([CH3:17])[N:3]=2)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=4)=[C:22]([CH3:24])[O:21][N:20]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: CC1=CC(C)(B(O)O)NO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(C)c1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 77.3 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3,5-dimethylisoxazolboronic acid (178 mg, 1.25 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (60 mg, 77% yield). EIMS 311.1 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6]1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([C:13]1[CH:12]=[CH:11][C:10]2[O:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:14]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2c(c1)CCCO2
Reaction time: 3 h
Yield: 35.5 %

Procedure:
Aluminium chloride (III) (1.9 g, 14.25 mmol) was added portion wise at 0° C. to a solution of 3,4-dihydro-2H-1-benzopyran (9a) (450 mg, 3.35 mmol) and 2-chloroacetyl chloride (270 μL, 3.4 mmol) in dichloromethane (10 mL). After 3 hours, the mixture was quenched by a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/cyclohexane 40/60) to afford the desired product (9b) as a white yellow oil (250 mg, 1.19 mmol, 35%).
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[C:20]=[S:21]>C(Cl)Cl.CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:19][C:20]([NH2:1])=[S:21])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-(4-isothiocyanato-phenyl)-4-methyl-piperazine and stirring the reaction mixture at RT for 17 h. Title compound: ES-MS: 251.0 [M+H]+; major peak at tR=3.56 min (System 1); Rf=0.27 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:13]1[C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:38]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=5)=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9][NH:8][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc(C(F)(F)F)c5)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccc(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1

Procedure:
(2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl)-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 7-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.203 g, 388 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.072 g, 44%). MP=88-91° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.83 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.95 (d, 1H), 7.82 (m, 2H), 7.50 (m, 2H), 7.15 (t, 1H), 7.05 (d, 1H), 2.75 (br m, 9H). MS=424 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1ccc2cc(O)ccc2n1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
6-hydroxy-2-methylquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-((trans)-4-tert-butylcyclohexyloxy)-2-methylquinoline, which in turn was oxidized with tert-butyl hydrogen peroxide and selenium dioxide in dioxane, providing 6-((trans)-4-tert-butylcyclohexyloxy)-2-formylquinoline. This aldehyde was then treated with t-butyl 3-aminopropionate and sodium cyanoborohydride in dichloroethane to afford t-butyl 3-(((6-(trans)-4-tert-butylcyclohexyloxy)-quinolin-2-yl)methyl)amino)propionate. Treatment with lithium hydroxide in methanol/THF gave the title compound, 3-((6-trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#N)[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:39]>C(Cl)Cl>[Cl:21][C:6]1[C:7]([CH3:20])=[C:8]([CH:18]=[O:39])[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (2.43 g, 7.95 mmol) in methylene chloride (50 mL) was added 1.0 M diisobutylaluminum hydride in hexane (19.9 mL, 19.9 mmol) at −78° C. The reaction was warmed to rt over 2 h with stirring. 5.0 M Hydrogen chloride in water (70 mL) was added slowly, and stirring was continued for 1 h. The resultant mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.4 g, 97%). LCMS calculated for C16H12ClF2O (M-OH)+: m/z=293.1; Found: 293.1.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:8][CH2:9][CH:10]([NH2:12])N)[CH:5]=[CH:6][N:7]=1)[CH3:2].[OH-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:12][CH2:10][CH2:9][CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])=[O:21])=[CH:18][CH:17]=1
Reactant: CCc1nccn1CCC(N)N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nccn1CCCNC(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.3 g. of 2-ethyl-1H-imidazole-1-propanediamine, 15 ml. of 2N sodium hydroxide and 150 ml. of methylene chloride was stirred at room temperature and 4.0 ml. of 4-chlorobenzoyl chloride was added. The reaction mixture was stirred for 18 hours, then methylene chloride and 15 ml. of 1N sodium hydroxide were added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The crystalline residue was washed onto a filter with ether and melted at 120°-122° C.
Reaction SMILES: [F:1][C:2]([F:18])([CH3:17])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:34][CH3:35])[C@@H:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)[OH:22]>>[F:18][C:2]([F:1])([CH3:17])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5](=[O:7])[NH:19][C@H:20]([C:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)=[O:22])[CH2:34][CH3:35]
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Product: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCOCC1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
By proceeding in a similar manner to Example 1 above but using (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-pentanoic acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol there is prepared Morpholine-4-carboxylic acid {(S)-3,3-difluoro-1-[(S)-1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propylcarbamoyl]-but}-amide as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.[C:15]([O-:18])([O-])=[O:16].[Na+].[Na+].BrBr>[Fe].C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:3]#[C:4][C:13]3[CH:8]=[CH:9][C:10]([C:15]([OH:18])=[O:16])=[CH:11][CH:12]=3)[CH:12]=2)[O:7][CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COCC1(C)CCOc2ccccc21
Agent: [Fe]
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Product: COCC1(C)CCOc2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 0 °C
Reaction time: 0.6 h
Yield: 95 %

Procedure:
2.00 g (10.4 mmol) of 4-methoxymethyl-4-methyl-chroman was dissolved in 25 ml of abs. CH2Cl2 and treated with a catalytic amount of Fe-powder and Na2CO3. After cooling to 0° C., 1.21 m of bromine (1.1 eq.) was added and the mixture kept for 0.6 h at this temperature. Pouring onto crushed ice, extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, filtration and evaporation of the solvents, and ensuing flash chromatography over SiO2 (hexane/ethylacetate 95/5) yielded 1.676 g of pure title compound as colorless oil (GC>95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[N:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1cccnc1
Temperature: 75 °C
Yield: 75.7 %

Procedure:
Pd(PPh3)4 (1.05 g, 0.91 mmol) was added to a to a solution of 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (2.0 g, 6.8 mmol), 4-carboxyphenylboronic acid (1.12 g, 6.7 mmol), and sodium carbonate (2.88 g, 27.2 mmol) in tetrahydrofuran/water, (1:1, 240 mL), and the resulting mixture was heated at 75° C. for 16 days. The solvent was evaporated and the residue dissolved in water. The aqueous phase was washed with ethyl acetate and then neutralized (pH 7) using HCl (10% aq.). The formed crystals were filtered off and dried in vacuo to give 1.7 g (77% yield) of the title compound: MS (ES) m/z 336 (M++1).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[CH:16](O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:16]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:2])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O
Yield: 43 %

Procedure:
40.8 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal and 17.0 g of diethyl acetylenedicarboxylate are treated in the same manner as described in Example 1-(3) to give 1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene. Yield: 43%
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH3:17]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:17]
Reactant: N#Cc1ccccc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1C#N

Procedure:
25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[CH3:41][C@H:42]1[C@H:47]([NH2:48])[CH2:46][C@@H:45]2[CH2:49][C@H:43]1[C:44]2([CH3:51])[CH3:50]>>[CH3:41][C@H:42]1[C@H:47]([NH:48][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])[CH2:46][C@@H:45]2[CH2:49][C@H:43]1[C:44]2([CH3:50])[CH3:51]
Reactant: C[C@H]1[C@H](N)C[C@@H]2C[C@H]1C2(C)C
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N[C@@H]4C[C@@H]5C[C@H]([C@H]4C)C5(C)C)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 69.1 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.089 g, 0.148 mmol) was reacted with (1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 30 μL, 0.179 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.075 g, 68%). m/z=733 (M+1); HRMS: calcd for C39H59ClFN4O4S. Calc [M+H+] 733.3924. found 733.3920.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:13].CN(CCN(C)C)C.[I:32]I>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:32])=[C:7]2[C:3]=1[CH:4]([OH:23])[N:5]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:6]2=[O:13]
Reactant: COc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 84.6 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (300 mg, 0.904 mmol) was dissolved in THF (12 mL), and the solution was treated with TMEDA (0.30 mL, 2.0 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 2.0 mL, 2.0 mmol) and iodine (275 mg, 1.08 mmol), followed by purification by slurry using diisopropylether and hexane to obtain 4-chloro-5-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (350 mg, yield 85%).