Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21]([C:28]#[N:29])[CH:22]=[C:23](B(O)O)[CH:24]=1>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:23]3[CH:22]=[C:21]([CH:20]=[C:19]([F:18])[CH:24]=3)[C:28]#[N:29])[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 5-fluoro-3-cyanophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.74 (s, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.94 (dt, J=11.7, 2.2 Hz, 1H), 3.28 (s, 3H), 2.01 (m, 4H), 0.82 (t, J=8.3 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−). Anal. calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C, 64.95; H, 5.42; N, 11.05.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=3[N:31]=2)=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:14][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[S:28][C:29]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[CH:25][CH:26]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCC(F)(F)F)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 4-(2,2,2-trifluoroethoxy)benzoic acid (0.30 g, 1.35 mmol) and thionyl chloride (0.32 g, 2.72 mmol) in chloroform (5 ml) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.34 g, 1.35 mmol) in dry pyridine (15 ml) to give the title compound (0.56 g, 91%) as a pale yellow solid after work-up.
Reaction SMILES: C([C:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:40])([F:39])[CH:36]([F:38])[F:37])[CH:29]=1)([CH:12]([OH:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[C:9]([OH:11])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:26][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:40])([F:39])[CH:36]([F:38])[F:37])[CH:29]=1)[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)C(Cc1ccccc1)(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1

Procedure:
To a solution of benzyl 3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoic acid (5.07 g, 9.09 mmol, crude) in ethanol (500 ml) was added 10% palladium/carbon (containing water by 50%) (500 mg), and the mixture was stirred overnight under a 1 atm hydrogen stream. The reaction solution was filtered with celite, and the filtrate was concentrated to give the objective substance (4.22 g, 100%, crude). The present compound was used for the next reaction as a crude compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[O:30]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[OH:30]
Reactant: COc1cc(-c2n[nH]cc2-c2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)c(O)c3)n2)c1
Temperature: 0 °C

Procedure:
3-{4-[3-(4-Chloro-3-methoxy-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzenesulfonamide (Example 40) (94 mg, 0.2057 mmoles) is suspended in CH2Cl2 (20 mL) and cooled to −0° C. BBr3 (0.5 mL, 1M in CH2Cl2) is added dropwise at −0° C. After 10 min the suspension is warmed to rt and kept at that temperature overnight. The reaction is quenched with 1 mL of water and the reaction mixture is concentrated. The residue is chromatographed on SiO2 (3% methanol/CH2Cl2) affording the title compound: ES-MS 443.1 [M+H]; single peak at tR=4.318 min (System 3); Rf=0.53 (100% EtOAc).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Reactant: CCCC(OC)(OC)OC
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 29.2 %

Procedure:
The general method described in Step 6 of Example 22 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (9.1 g, 28.9 mmol) by reaction with trimethyl orthobutyrate (4.4 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinoline (3.10 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: N1CCOCC1.[C:7]([C:9]1[C:14]([CH:15]2[CH2:17][CH2:16]2)=[CH:13][C:12](=[O:18])[NH:11][C:10]=1[SH:19])#[N:8].Br[CH2:21][C:22]([NH2:24])=[O:23]>CN(C=O)C>[C:7]([C:9]1[C:14]([CH:15]2[CH2:16][CH2:17]2)=[CH:13][C:12](=[O:18])[NH:11][C:10]=1[S:19][CH2:21][C:22]([NH2:24])=[O:23])#[N:8]
Reactant: N#Cc1c(C2CC2)cc(=O)[nH]c1S
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: N#Cc1c(C2CC2)cc(=O)[nH]c1SCC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
3-Cyano-4-cyclopropyl-6-oxo-1,6-dihydro-pyridine-2-thiol morpholine salt (15.00 g, 53.69 mmol) was suspended in 15 mL of dry DMF. 2-Bromoacetamide (7.74 g, 55.0 mmol) was added. This mixture was stirred at room temperature for 30 min and quenched with water. The resultant solid was collected by filtration, washed with water and dried under high vacuum for 24 h to give 2-(3-cyano-4-cyclopropyl-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl)-acetamide as a pale colored solid (13.22 g, 99%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:19]([S-])=[S:20])C.[K+].C(O)C>O>[S:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl)propionate as a brown oil which was shown to be a single compound by thin layer chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:20]([F:26])[CH:19]=2)=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)c(F)c1
Reactant: C1CCNC1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared as example 1.1b from 105 mg (0.24 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 16h) and 0.06 mL (0.73 mmol) pyrrolidine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2nc(CN3CCCCC3)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 64.6 %

Procedure:
A mixture of 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (2.0 g), piperidine (2.27 g) and ethanol (40 ml)--dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and dichloromethane (50 ml) was added to the residue. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (1:1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%). This compound was recrystallized from ethyl acetate - hexane. Colorless needles, mp. 130°-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](=O)[CH3:13].Cl>C(O)(C)C.C(OCC)(=O)C>[CH3:12][CH:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: CC=O
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1Nc2cccnc2S(=O)(=O)N1

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.28 g of acetaldehyde in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, a crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The 3-methyl-2,3-dihydro-4H-pyrido[3,2- e] [1,2,4]thiadiazine 1,1-dioxide is recrystallized from a CH3OH/H2O (1/4) mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([S:12][CH3:13])=[N:5][CH:6]=[N:7]2.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=O)C1.[N:34]([C@@H:37]1[CH2:42][CH2:41][NH:40][CH2:39][C@H:38]1[OH:43])=[N+:35]=[N-:36]>C(Cl)(Cl)(Cl)Cl>[N:34]([C@@H:37]1[CH2:42][CH2:41][N:40]([CH2:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([S:12][CH3:13])=[N:5][CH:6]=[N:7]3)[CH2:39][C@H:38]1[OH:43])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=N[C@@H]1CCNC[C@H]1O
Reactant: CSc1ncnc2cccc(C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnc2cccc(CN3CC[C@@H](N=[N+]=[N-])[C@H](O)C3)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a mixture of 1C (1.19 g, 6.25 mmol), AIBN (111.2 mg, 0.625 mmol), and NBS (1.129 g, 6.875 mmol) under N2 was added CCl4 (30 ml). The mixture was degassed under vacuum, purged with nitrogen (2×) and heated to 80° C. for 40 min. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloroethane (30 ml). (3R,4R)-4-azidopiperidin-3-ol (976 mg, 6.875 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (1.04 ml, 7.5 mmol) were subsequently added. The mixture was stirred at room temperature for 1 h, then at 75° C. for 30 min. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO3, then extracted with 2N HCl (40 ml). The acidic aqueous layer was separated and basified with 50% NaOH. Solid product was collected by filtration, washed with water and dried under high vacuum to give 1D (1.51 g, 73%) as a solid. The compound has an analytical HPLC retention time=1.106 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=331+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([CH:23]=[O:24])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[Si]([C:29]#[N:30])(C)C.Cl>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:24][CH:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:12]1=[N:13][O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[C:11]1[CH2:22][CH2:21]2)[C:29]#[N:30]
Reactant: C[Si](C)(C)C#N
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C#N)ccc2-3)cc1
Yield: 98.7 %

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 11C, 250 mg, 0.78 mmol) in dichloromethane (4 mL) at 0° C. was added trimethylsilyl cyanide (0.13 mL, 0.94 mmol) and titanium(IV) isopropoxide (0.46 mL, 1.6 mmol). The reaction mixture was stirred for 1 h before 1 N HCl (aq) was added along with additional dichloromethane. The organic layer was dried (over magnesium sulfate), filtered, and concentrated to give crude 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (Preparation 127A, 265 mg, 0.77 mmol, 98% yield): LC/MS M+1=345.1.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[CH2:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:16])[CH3:15]
Reactant: Fc1cccc2c1CNCCS2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1CCSc2cccc(F)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.04 g, prepared in a similar manner to its hydrochloride, Example 3 above) in acetic anhydride (22 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (97:3) as eluent gave 4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil. Yield 1.7 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:15]#[N:16])[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]#[N:9])[CH3:2].[S:18](=[O:22])(=[O:21])([OH:20])[OH:19].COCCOC>[OH-].[Pd+2].[OH-].[C].C(N(CC)CC)C>[S:18]([OH:22])([OH:21])(=[O:20])=[O:19].[NH2:9][CH2:8][C:7]1[C:6]([C:15]#[N:16])=[C:5]([F:17])[C:4]([O:3][CH2:1][CH3:2])=[C:11]([O:12][CH2:13][CH3:14])[CH:10]=1
Reactant: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Agent: [Pd+2]
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOc1cc(CN)c(C#N)c(F)c1OCC
Temperature: -22 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 4,5-diethoxy-3-fluorophthalonitrile (2.34 g, 10 mol) prepared in Preparation Example 1, sulfuric acid (0.56 mL, 10 mol), 20% palladium hydroxide-carbon (0.59 g, 50% hydrate) (20% palladium-carbon powder, palladium hydroxide type (hydrate), N.E. Chemical Corporation) and 1,2-dimethoxyethane (23 mL) was stirred at −22° C. under hydrogen atmosphere (atmospheric pressure) for 24 hours. After insoluble matter in the reaction mixture was filtered off, the residue was washed with methanol (23 mL) and the combined filtrate was divided into five equal portions. After one of them was concentrated at room temperature under reduced pressure, 1,2-dimethoxyethane (9.2 mL) was added thereto, and the mixture was stirred. Then, triethylamine (0.56 mL, 4 mol) was added dropwise thereto and the mixture was stirred at room temperature for one hour. Precipitated crystals were filtered, washed with a 5% methanol-1,2-dimethoxyethane solution, and dried at room temperature under reduced pressure to give 0.59 g of the ½ triethylamine solvate of the title compound (yield: 76%) as dark white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[C:10]([Cl:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:15](=[O:17])[CH3:16])[C:10]([Cl:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC

Procedure:
A mixture of 21 g of methyl 2-methoxy-4-amino-5-chlorobenzoate is stirred in 12 ml acetic anhydride and 100 ml acetic acid at 100° C. for 24 hours. The reaction mixture is filtered, diluted with water, filtered and evaporated to dryness to obtain methyl 2-methoxy-4-acetylamino-5-chlorobenzoate which is used directly in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].Cl[C:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=[C:15]([Cl:24])[CH:14]=1.Cl>CCO>[Cl:24][C:15]1[CH:14]=[C:13]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1
Yield: 68 %

Procedure:
2-Naphthylamine and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, yielding ethyl 6-chloro-4-(2-naphthylamino)nicotinate (68%). 1H NMR [400 MHz, (CD3)2SO] δ 9.91 (br s, 1H), 8.71 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 3H), 7.59-7.48 (m, 3H), 6.91 (s, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][NH:15][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC(C(=O)OC)c1ccc(CN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)OC)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of 2-(4-aminomethyl-phenyl)-pent-4-enoic acid methyl ester (1.67 g, 6.55 mmol) in dichloromethane (50 cm3) at ambient temperature under an atmosphere of dry nitrogen was added triethylamine (4.56 cm3, 32.8 mmol) followed by dropwise addition of methanesulfonyl chloride (1.52 cm3, 19.7 mmol) over 5 minutes. The mixture was stirred for 4 hours at ambient temperature and the filtrate volatile fractions removed in vacuo to afford a crude yellow oil. The oil was dissolved in ethyl acetate (100 cm3), washed with saturated sodium bicarbonate (2×50 cm3), brine (25 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a crude yellow oil. The oil was purified by column chromatography (silica, eluting with hexane-ethyl acetate 4:1 to 1:1) to afford the title compound as a pale yellow viscous oil (1.85 g, 100%) with a positive ion ESI (M+H)+296.2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccc(F)c1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(F)c2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-fluorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-fluorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:25].[Na+]>CC(=O)CC>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][I:25])[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccc(OCCI)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 10 mL of 2-butanone was added sodium iodide (8.73 mmol, 1.31 g). The solution was heated at reflux for 48 hours, cooled to room temperature, and concentrated to afford the crude product, 5-(2-iodo-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester: MS(APCI+): m/z 436.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([C:16]([O:18]C)=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6].O[Li].O>CO.O>[CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([C:16]([OH:18])=[O:17])[NH:4][C:5]([O:7][C@@H:8]1[CH2:10][C@H:9]1[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])=[O:6]
Reactant: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C=CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl 3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinate in 2:1 mixture of MeOH/H2O was treated with LiOH.H2O (4 eq) and then heated at 60° C. for 4 h. The mixture was cooled and concentrated to half volume, then diluted with EtOAc and acidified with aqueous HCl (1 N). The organic layer was separated and washed with brine then dried. Removal of the volatiles afforded the title compound (98%) as an oil. MS (ES+) m/z 284 (M+H)+